Antibiotic-Resistant Bacteria - ACS Publications - American Chemical

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Antibiotic-Resistant Bacteria: Prevalence in Food and Inactivation by Food-Compatible Compounds and Plant Extracts Mendel Friedman* Western Regional Research Center, Agricultural Research Service, U.S. Department of Agriculture, Albany, California 94710, United States ABSTRACT: Foodborne antibiotic-resistant pathogenic bacteria such as Campylobacter jejuni, Bacillus cereus, Clostridium perfringens, Escherichia coli, Salmonella enterica, Staphylococcus aureus, Vibrio cholerae, and Vibrio parahemolyticus can adversely affect animal and human health, but a better understanding of the factors involved in their pathogenesis is needed. To help meet this need, this overview surveys and interprets much of our current knowledge of antibiotic (multidrug)-resistant bacteria in the food chain and the implications for microbial food safety and animal and human health. Topics covered include the origin and prevalence of resistant bacteria in the food chain (dairy, meat, poultry, seafood, and herbal products, produce, and eggs), their inactivation by different classes of compounds and plant extracts and by the use of chlorine and physicochemical methods (heat, UV light, pulsed electric fields, and high pressure), the synergistic antimicrobial effects of combinations of natural antimicrobials with medicinal antibiotics, and mechanisms of antimicrobial activities and resistant effects. Possible areas for future research are suggested. Plant-derived and other safe natural antimicrobial compounds have the potential to control the prevalence of both susceptible and resistant pathogens in various environments. The collated information and suggested research will hopefully contribute to a better understanding of approaches that could be used to minimize the presence of resistant pathogens in animal feed and human food, thus reducing adverse effects, improving microbial food safety, and helping to prevent or treat animal and human infections. KEYWORDS: microbial food safety, antibiotic-resistant bacteria, multidrug-resistant bacteria, susceptible bacteria, prevalence in food, animal feed, human food, organic food, infectious disease, inactivation, resistant mechanisms, antimicrobial mechanisms, quorum sensing, bacterial SOS response, research needs

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INTRODUCTION Antibiotics are primarily used to treat human and animal infections; however, they are also used to promote growth of livestock and poultry.1 The use of antibiotics in food-producing animals such as cattle and pigs often results in the emergence of antibiotic resistance in foodborne pathogens (e.g., Campylobacter, Escherichia coli, and Salmonella).2,3 Resistant microorganisms that often arise from the use of antibacterial soaps and sanitizers, the administration of subtherapeutic levels and overprescription of antibiotics, and widespread use in livestock are worldwide concerns.4−7 Table 1 and the cited references

There is increasing concern about the growing number of foodborne illness outbreaks caused by some pathogens, coupled with the antibiotic resistance associated with foodborne infections. There has therefore been interest in developing new types of effective and safe antimicrobial compounds derived from natural sources. For example, as part of an effort to develop antimicrobial food formulations that will protect both the food and the consumer against pathogenic bacteria, we have evaluated the bactericidal activities of ∼300 potential antimicrobials, including essential oils, oil components, phenolic benzaldehydes and benzoic acids, teas and their catechins and theaflavins, wines and isolated wine compounds, and chitosan, against one or more of the following foodborne pathogens: Bacillus cereus, Campylobacter jejuni, Clostridium perfringens, Escherichia coli O157:H7, Listeria monocytogenes, Mycobacterium avium subspecies paratuberculosis, Salmonella enterica, and Staphylococcus aureus.9−13 Many of the phytochemicals and plant extracts are active against both nonresistant (susceptible) and antibiotic-resistant (resistant) bacteria in buffers and in liquid and solid foods. There is a need to develop new, preferably inexpensive, alternatives for standard antibiotics for use against antibioticresistant bacteria, providing more options for the treatment of

Table 1. Most Common Foodborne Bacteria with Antibiotic Resistance in the United States in 20118 pathogen Campylobacter Salmonella (nontyphoidal) Salmonella Typhi Shigella

illnesses/ year 1,300,000 1,200,000 5,700 500,000

% resistant 24% azithromycin or ciprofloxacin 8% any pattern (ciprofloxacin 3%, ceftriaxone 3%, MDR 5%) 67% ciprofloxacin 6% azithromycin or ciprofloxacin

show that in the United States, the four major foodborne pathogens with antibiotic resistance are nontyphoidal Salmonella, Salmonella Typhi, Campylobacter, and Shigella, which possibly contribute to infections of ∼2 million people annually that cannot be treated with antibiotics, resulting in about 23,000 deaths.5,8 This article not subject to U.S. Copyright. Published XXXX by the American Chemical Society

Received: December 9, 2014 Revised: March 31, 2015 Accepted: April 1, 2015

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DOI: 10.1021/acs.jafc.5b00778 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Journal of Agricultural and Food Chemistry

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(VRE) were not detected in any of the samples; (d) S. aureus isolates showed the highest resistance to ampicillin and tetracycline; and (e) three C. jejuni isolates from a hospital patient with diarrhea and two chicken samples that exhibited resistance to ciprofloxacin had identical pulsed-field gel electrophoresis patterns, suggesting that the resistant pathogen could have originated from the chicken meat.17 This study shows that the prevalence of MRSA and VRE was low in foodproducing animals and domestic meats in Japan. It also provides a good example of how and why antimicrobialresistant pathogens should be monitored regularly to improve the management of the antimicrobial drug resistance associated with their transfer from food-producing animals to humans. Related studies indicate that (a) resistant E. coli can contaminate meat products during slaughter and enter the food chain regardless of whether or not cattle are administered the antimicrobial growth promoter (AGP) chlortetracycline plus sulfmethazine, with most isolates from meat and environmental samples having similar genetic profiles to hides or digesta;18,19 (b) a probable relationship exists between swine and human salmonellosis across the food chain;20 and (c) banning the use of growth-promoting antibiotics seemed to result in decreases in the prevalence of some resistant bacteria in food animals.21 The method by which antibiotics are administered to humans or animals could potentially affect the levels of resistant bacteria. For example, a study by Zhang et al.22 found that oral administration of the medicinal antibiotics ampicillin and tetracycline to mice resulted in increased levels (amplification and development) of antibiotic resistance (AR) in the gut microbiota. The effect may be minimized by intraperitoneal (ip) injection of the antibiotics. Other Animals. A survey by Gorski et al.23 of cold-blooded vertebrates (frogs, lizards, newts, salamanders, snakes, and toads) and associated surface waters in a produce-growing region of California to determine the diversity of Salmonella found that 66 isolates of 460 samples from amphibians and 119 water samples showed resistance, with 27 isolates resistant to more than one antibiotic and 6 isolates to three classes. The authors suggest that these species may serve as reservoirs of antibiotic resistance, determinants in the environment, and sources of contamination of leafy greens associated with produce recalls. Related studies found that fecal samples of birds and mammals may function as host reservoirs and potential vectors for the spread of resistant E. coli bacteria24 and that the feces of stray dogs and coyotes are also a potential reservoir of resistant E. coli and Salmonella strains.25 There is, therefore, a need for good agricultural practices to mitigate microbial risks from animal fecal deposits, especially in produce production areas. Fresh Fruits and Vegetables. A review of the literature suggests that reducing microbial contamination of irrigation water and soil may help prevent and control produce contamination to produce (such as leafy greens and tomatoes).26 A study by Oliveira et al.27 on the transfer of E. coli O157:H7 from soil fertilized with contaminated compost or irrigated with contaminated water to the edible part (leaves) of lettuce indicates that microbial contamination takes place from both sources and persists for several months.28 Holvoet et al.29 reported a moderate prevalence of antimicrobial resistance in E. coli isolates from lettuce, irrigation water, and soil. A survey of 29 commercial herbal supplements showed that tetracycline-resistant bacteria in onion powders and ground

livestock and poultry and reducing the exposure of humans to resistant bacteria. A challenging objective is to develop candidates that could be incorporated into natural, safe formulations to reduce both susceptible and resistant pathogens in animal feeds, food-animal environments, and human foods. With this aim in mind, a critical assessment by Wright,14 and additional publications mentioned below, describe the potential impact natural products could have on antibiotic drug discovery. There is general agreement that antibiotic discovery is in crisis and that the discovery of new natural-product-based antibiotics that can also combat the problems of resistance is needed urgently. To help stimulate the research needed to achieve these objectives, this review strives to integrate the widely scattered information on the origin, distribution in the food chain, and proposed approaches to inactivate resistant pathogens and the mechanisms of antimicrobial and resistant effects. Work so far, described here, provides a scientific basis, resource, and rationale for future progress designed to mitigate the adverse potential of resistant pathogens in animal feed, human food, and infectious diseases. Although the present review is largely limited to resistant pathogens, related aspects about susceptible organisms will be mentioned for comparison. The availability of novel and safe antibiotics provides more options for the treatment of livestock, poultry, animal feed, and human food and reduces the exposure of humans to resistant bacteria.

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OCCURRENCE OF ANTIBIOTIC-RESISTANT BACTERIA IN THE FOOD CHAIN Antibiotic-resistant bacteria are prevalent in different environments and can therefore be introduced into the food chain at different points. Here we will briefly describe the prevalence of antibiotic-resistant bacteria in the food chain. Humans and Livestock. When the impact of resistant bacteria on the food chain is considered, an important area for investigation is people coming into contact with livestock and farms who are at risk of infection by antibiotic-resistant bacteria that are present in that environment. For example, a study in Thailand15 found that, among 544 healthy adult food factory workers, 75% were positive for a particular resistant bacterium of interest, extended-spectrum β-lactamase (ESBL)-producing E. coli. The value for 30 healthy animal farm workers was 77.3%. Among the farm animals, the value was 76.7% in pigs and 40% in poultry broilers. The ESBL-producing E. coli was more prevalent in fresh meat samples than in fresh vegetables, in fresh than in cooked foods, and in water samples collected from animal farms than in those from canals and fish and shrimp ponds. A study has also been conducted on the short-term exposure to resistant bacteria of 30 veterinary students on 40 pork farms, in which nasal swabs of the students and pigs were taken before and after the farm visits.16 The findings of the study include that (a) methicillin-resistant Staphylococcus aureus (MRSA) was present in 30% of the pork farms and 22% of the students; (b) all students found to be MRSA-positive were initially negative; and (c) because the duration of MRSA exposure was brief, it most likely represents contamination of the nasal passages rather than biological colonization.16 A Japanese study on the prevalence of resistant pathogens from retail meats and food-animal feces found that (a) resistance to Campylobacter coli was higher than to Campylobacter jejuni; (b) MRSA was isolated from 3% of the meat samples (9 of 300); (c) vancomycin-resistant Enterococci B



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(27.9%).43 Related studies on the prevalence of resistant pathogens in retail raw poultry in China are described by Yang et al.,44 in Italy by Giacomelli et al.,45 in Nigeria by Raufu et al.,46 in the United Kingdom by McNeece et al.,47 and in Vietnam by Ta et al.48 It is noteworthy that Sapkota et al.49,50 observed lower levels of resistant bacteria in poultry farms in the United States that transitioned to organic practices without the use of antibiotics. A review of the literature by Smith-Spangler et al.51 indicates that the risk of isolating bacteria resistant to three or more antibiotics was higher in conventional than in organic chicken or pork (risk difference 33%). By contrast, the study by Mollenkopf et al.52 on resistant E. coli pathogens in organic (antibiotic-free) fresh retail chicken breast does not seem to support this conclusion, suggesting further studies are needed. Because the consumption of poultry meat is reported to be a major source for foodborne diseases, Adzitey et al.53 examined the prevalence of resistant Campylobacter, Salmonella, and Listeria isolated from ducks. The mean prevalence for Campylobacter is 53% in ducks, 31.6% in duck meat, and 94.4% in the duck-rearing and -processing environment; the lower values recorded for Salmonella suggest that ducks were more frequently contaminated with Campylobacter than with the other bacteria. Collectively, the cited studies show that raw and processed poultry products are a major source of resistant pathogens. Other Food Products. Other studies have been carried out on specific food groups or a range of food groups for comparison. For example, to help define the problem of antibiotic resistance in E. coli, the most common Gram-negative pathogen in humans, across a range of food types, Rasheed et al.54 used the Kirby−Bauer method to determine the antibiotic sensitivity patterns of different foods collected randomly in India. The highest level of resistant bacteria (in %) was found in raw chicken (23.3), followed by vegetable salad (20), raw meat (13.3), raw egg surface (10), and unpasteurized milk (6.7), with an overall incidence of drug-resistant E. coli of 14.7. The authors suggest that, because pathogen cycling through food is common, it might pose a potential health risk to the consumer. The results of a related study from Bangladesh suggested that RTE frozen food contaminated with susceptible and resistant bacteria could be a potential vehicle for transmitting foodborne disease.55 An evaluation in Poland of the resistant profile of Staphylococcus spp. isolated from 858 RTE foods (cheeses, cured meats, sausages, smoked fish, salads) found that 54.9% of the isolates were resistant to at least one class of antibiotics, and, of these, 35.4% of the strains were multidrug resistant, suggesting that RTE food is an important route for the transmission of resistant bacteria.56 Fish and shellfish are reported to contain resistant pathogens. 57−60 Duran and Marshall 61 found that 13 commercial brands of RTE shrimp contained high levels of multiple resistant bacteria. The authors suggest that thawing of shrimp products before serving may result in consumer exposure to resistant bacteria and that the worldwide trade of shrimp products may help disseminate resistant pathogens. Although the incidence of resistant bacteria has been found to be higher in retail meat (69.8%) than in dairy (62.5%) products,62 many studies that have included dairy products have reported the presence of resistant organisms in retail cheeses, salads, ham, and raw meat,63 in cow’s milk and dairy products,64 in goat’s and sheep’s milk,65 and in Gouda cheese manufactured from raw milk.66 The cited authors emphasize

garlic samples and that ginger, goldenseal, mustard, and rosemary contained low levels of resistant bacteria.30 Related studies report that (a) raw tomatoes are a potential exposure risk for resistant Enterococcus spp.;31 (b) Brazilian ready-to-eat (RTE) salad vegetables contained resistant Salmonella enterica isolates;32 (c) factors other than streptomycin exposure seem to be responsible for resistant bacteria in apple orchards;33 and (d) the use of fungicides such as fludioxonil for gray mold control in blackberries and strawberries may be a risk for the development of resistant strains in European and North American fields.34 Meat and Meat Products. Once livestock has been slaughtered to process into meat and meat products, the problem of antibiotic resistance remains. An Austrian study on the prevalence and genetic characteristics ESBL-producing bacteria, MRSA, and VRE reported the presence of 24 ESBL isolates in 20 of the 100 minced meat samples from a butcher’s shop.35 A Chinese study found that 210 samples collected from a large-scale swine farm contain MDR bacteria that could be transmitted to humans.36 The large diversity of ESBLproducing E. coli may indicate a growing dissemination of ESBL genes in this microorganism from bovine and porcine origins. A comprehensive review of the literature on the worldwide presence of livestock-associated MRSA indicates that (a) the slaughter process plays a decisive role in MRSA transmission from farm to fork; (b) heat treatment such as flaming and scalding during the slaughter process can significantly reduce the MRSA burden on carcasses; and (c) recontamination with MRSA might occur as a result of fecal contamination at evisceration or by human handling during meat processing.37 These steps can be improved to minimize the transmission of MRSA from pig to pork. Poultry Products. Poultry can also be a reservoir for resistant bacteria that can be transmitted to humans. There have therefore been studies conducted on the prevalence and characterization of resistant bacteria in poultry. For example, to assess whether the food chain might contribute to the epidemiology and the transmission of cephalosporin-resistant E. coli, Abgottspon et al.38 used antibiotic susceptibility testing to characterize resistant bacteria isolated from domestic and imported poultry meat. They found that 21 of the 24 isolates were multidrug resistant and that multilocus sequence and phylogenetic group typing indicated a high heterogeneity among different isolates of the same sample. A German study39 found that E. coli from human stool samples was more resistant than chicken isolates, suggesting that a comparison of ESBL and the multilocus sequence type of the human and poultry isolates are not correlated and that chicken meat is not a major contributor to the colonization of ESBL-carrying Enterobacteriaceae in humans. The results of a Canadian study40 on the resistance of 193 Salmonella Enteritidis, Hadar, and Typhimurium serovars isolated from broiler production facilities indicated that >43% of the isolates were resistant to multiple antibiotics and that the resistant serovars were genetically diverse, suggesting that the presence of these strains is highly relevant to food safety and public health. A Romanian study found that 23% of 144 chicken carcasses contained MDR E. coli and Salmonella strains.41 A Greek study on E. coli found in meat from retail stores showed that isolates from chicken had higher levels of resistance to ciprofloxacin (62.5%) than those in lamb/goat isolates,42 which in turn were higher than those in beef isolates C



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bacteria can, in principle, evolve resistance to any antimicrobial, it is important to use antibiotics and alternatives judiciously72 and to determine whether proposed new antimicrobials develop resistance in bacteria. Many types of food and other natural products have been used for medicinal purposes for centuries; indeed, most drugbased antibiotics have been based on or derived from natural products. With the increase in antibiotic resistance, the interest in using the natural products themselves as antibiotics has increased. As an example of such a study, in 2004, we reported on the ability of five selected natural products to inhibit three resistant pathogens.12 After demonstrating the lack of effectiveness of standard antibiotics against the acquired antibiotic resistance of B. cereus (NCTC10989), E. coli (NCTC1186), and S aureus, we showed that the following natural substances inhibited these three resistant pathogens: cinnamon oil, oregano oil, thyme oil, carvacrol (a major component of oregano and thyme oils), (S)-perillaldehyde, 3,4dihydroxybenzoic (β-resorcylic acid), and dopamine (3,4dihydroxyphenylethylamine).12 Exposure of the three pathogens to a dilution series of the test compounds showed that oregano oil was the most active substance. The oils and pure compounds exhibited exceptional activity against B. cereus vegetative cells, with oregano oil being active at nanogram per milliliter levels. In contrast, activities against B. cereus spores were low. Activities of the test compounds were in the following approximate order: oregano oil > thyme oil > > carvacrol (the main constituent of oregano oil) > cinnamon oil > perillaldehyde > dopamine > β-resorcylic acid. The order of susceptibilities of the three pathogens to inactivation was B. cereus > S. aureus > E. coli. The cited results show that all test substances were active, and some were highly active, against the resistant organisms. In a related study, we found that the above-mentioned substances had bactericidal activity against a resistant nonpathogenic Micrococcus luteus strain.90 Unlike the many standard antibiotics evaluated, all of the compounds were active against this organism. This organism can be used as a model to test the efficacy of potential antimicrobials against resistant bacteria. Other investigators reported that the combination of five molecules (trans-cinnamaldehyde, βresorcylic acid, carvacrol, thymol, and eugenol) was more effective than individual compounds in overcoming resistant Salmonella enterica to one or more antibiotics, suggesting that the natural compounds could potentially be used as feed supplements to reduce antibiotic resistance in food animals.91 The papers by Gibbons et al.92 and Oluwatuyi et al.93 and the above-cited study seem to have been some of the first reports on the inhibition of resistant pathogens by natural compounds and plant extracts. A discussion of the use of such essential oils is continued in the section below on essential oils and their constituents.

the need to use improved hygienic conditions to reduce the prevalence of resistant bacteria in dairy products. The resistance of egg shell Salmonella isolates, especially Salmonella Typhimurium, to antimicrobial drugs was shown to be serotype dependent and was greater than observed with E. coli isolates, suggesting the need to reduce resistant pathogens in shell eggs and shell egg processing water.67 In another study that involved a range of food types, Duffy et al.68 compared the survival of susceptible and resistant strains of E. coli in various food matrices. Orange juice and yogurt were inoculated with antibiotic-sensitive (AS) and laboratory-created antibiotic-resistant mutants (MAR) of E. coli O157:H7 or E. coli O26, and their growth/survival was monitored at 37 °C or in storage at 4 °C. The strains were also inoculated into minced beef and their D values (time in minutes for a 1 log reduction of the bacteria) examined at 55 °C, with and without a prior heat shock at 48 °C. The results show that (a) the growth kinetics in the laboratory were similar for both susceptible and resistant bacteria and (b) E. coli O157 MAR died out significantly more quickly in orange juice and yogurt and was more heat-sensitive than the other verocytotoxigenic (VTEC) strains. The authors discuss the possible reasons for the observed difference in survival between resistant and VTEC organisms.

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METHODS FOR TESTING BACTERIAL RESISTANCE Many of the studies cited above required methods for the rapid identification of resistant bacteria. Although not discussed in detail here, the development of assays used to detect atypical and multidrug resistance, especially in ESBL and carbapenemase-expressing Enterobacteriaceae, is of worldwide importance. Reviews by Frickmann et al.69 and Zboromyrska et al.70 discuss the advantages of rapid assays based on MALDI-TOF mass spectrometry in combination with PCR/electrospray ionization mass spectrometry or minisequencing. A simple, inexpensive, and easy-to-perform assay to screen antimicrobial compounds from natural products or synthetic chemical libraries for their potential to work in tandem with antibiotics against multiple drug-resistant bacteria is based on measuring zones of inhibition in Petri plates.71

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COMBATTING ANTIBIOTIC RESISTANCE WITH ALTERNATIVES TO TRADITIONAL MEDICAL ANTIBIOTICS Because the occurrence of resistant pathogens is still a problem, and yet the rate of development of new antibiotics has declined, Allen et al.72 suggest the need to discover alternatives to antibiotics used in both animal agriculture and human medicine. Suggested alternatives include modulating the gut microbial community, either through feed additives or fecal transplantation, phage therapy, phage lysins, bacteriocins, endolysins isolated from bacteria, and predatory bacteria as well as the alteration of the rumen population and fermentation with the aid of saponin plant glycosides and new natural antimicrobial compounds.73,74 Intervention (mitigation) strategies to reduce the prevalence of pathogens in sanitation facilities and in food animals have been described by Callaway et al.,75 White et al.,76 Clardy et al.,77 Wang et al.,78 Walsh and Fanning,79 Fischbach and Walsh,80 Doyle and Erickson,81 Doyle et al.,82 Hur et al.,83 Oliveira et al.,84 Capita and Alonso-Calleja,85 Rutkowski and Brzezinski,86 Allen et al.,72 Brown et al.,74 Gyawali and Ibrahim,87 Jassim and Limoges,88 and Linden et al.89 Because

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PURE NATURAL COMPOUNDS ISOLATED FOR USE AS ANTIBIOTICS I will now briefly describe in alphabetical order the resistant effects of pure compounds isolated from natural sources and plant extracts. In some cases, the studies on the plant extracts and their pure compounds are linked, so they are dealt with together. Baicalein. Baicalein is an active constituent isolated from the root of Scutellaria baicalensis. It is a flavonoid that has been used as a Japanese herbal supplement and has been shown to D



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significantly reverse ciprofloxacin resistance of MRSA.94 It may also be an SOS response inhibitor of S. aureus (see section below on the SOS response as an antibiotic target).95 Chlorogenic Acid. The phenolic compound chlorogenic acid is commonly found in many plant materials, including coffee beans, grapes, and tea. The isolated compound was shown to have antibacterial and antibiofilm activities against clinical isolates of Stenotrophomonas maltophilia, including a resistant strain.96 It could therefore be developed as a safe antibiotic alternative or for use in combination. Other Phenolic Compounds. An evaluation of the structure−activity relationship (SAR) of pure phenolic compounds isolated from several mushroom species using molecular docking studies showed that (a) 2,4-dihydroxybenzoic and protocatechuic acids inhibited MRSA more than methicillin-susceptible S. aureus; (b) MRSA was inhibited by 2,4-dihydroxybenzoic, vanillic, and syringic acids at MICs of 0.5 mg/mL and by p-coumaric acid at an MIC of 1 mg/mL; and (c) these compounds at the same concentrations did not inhibit methicillin-susceptible S. aureus, suggesting that the presence of COOH, two OH groups in the para and ortho positions, and an OCH3 group in the meta position of the benzene ring seems to govern anti-MRSA activity.97,98 We previously reported on a similar SAR study of these and related phenolic compounds against four susceptible pathogens.99 An evaluation of anti-Campylobacter activities by an MIC assay using microdilution coupled with ATP measurement showed that (a) the natural phenolic compounds of plant origin produced significant, but variable, activities against both resistant and susceptible Campylobacter; (b) carnosic and rosmarinic acids showed the highest activity in pure forms and in enriched plant extracts; and (c) inactivation of the efflux pump genes in Campylobacter mutants significantly increased antimicrobial activity, suggesting that the drug efflux systems contribute to the resistance to the phenolic compounds.100 Phenolic compounds have also been tested for their efficacy in treating fungal infections. A quantitative structure−activity relationship (QSAR) of 11 natural phenolic compounds against four fluoconazole-resistant Candida albicans species may make it possible to predict the anti-Candida activity of new phenolic compounds in the search for antifungal candidates.101 cis-Cinnamic Acid. Although both cis and trans isomers of cinnamic acid can be found in plants, the trans form is the more common. The transformation of trans-cinnamic acid to the cis isomer and isolation of cis-cinnamic acid allowed its antibacterial activity to be measured alone and in combination against resistant Mycobacterium tuberculosis.102 Although both isomers were active against the resistant strain, the cis isomer showed greater activity, suggesting its potential value to treat tuberculosis. Ellagitannins and Gallotannin. Ellagitannins, esters of hydrolyzable tannins, hexahydrodiphenoic acids, and monosaccharides, occur in fruits (blackberry, raspberry, strawberry, and pomegranate), nuts (almonds, walnuts), and seeds. A review by Lipińska et al.103 on bioactive ellagitannins includes a section on reported inhibition of MRSA by ellagitannins from black raspberry.104 A gallotannin (1,2,3-tri-O-galloyl-β-Dglucopyranose) isolated from the Terminalia chebula fruit exhibited efflux-pump inhibitory activity against multidrugresistant uropathogenic E. coli.105 Tannins from fruits and nuts merit further study for their potential to inhibit resistant bacteria.

Enterocin. The enterocins are bacteriocins that can be isolated from Enterococcus faecium. A test of the efficacy of the antimicrobial enterocin AS-48 alone and in combination with biocides such as benzalkonium chloride against three susceptible and three resistant S. aureus strains showed that (a) inactivation was greater in combination than with individual antimicrobials; (b) inactivation continued during storage; and (c) higher concentrations of antimicrobials were needed to inhibit the formation of biofilms.106 Because bacteriocins and related peptide antibiotics are active against susceptible pathogens,74,107 it would be interesting to determine whether or not they also inhibit resistant organisms. Human Milk Protein−Lipid Complex (HAMLET). Human α-lactalbumin made lethal to tumor cells (HAMLET) is a protein−lipid complex isolated from human milk that has both tumoricidal and bactericidal activities. Sublethal concentrations of HAMLET potentiated the antimicrobial effect of common antibiotics (penicillins, macrolides, and aminoglycosides) against pneumococci.108 A combination of HAMLET and antibiotics completely eliminated biofilms and colonization in mice of both susceptible and resistant strains of Acinetobacter baumanii and Moraxella catarrhal, suggesting the presence of a conserved HAMLET-activated pathway that circumvents antibiotic resistance in bacteria. Pentacyclic Triterpenoids. Three triterpenoids isolated from the bark of the tree Callicarpa farinosa inactivated MRSA and methicillin-sensitive S. aureus with MIC values ranging from 2 to 512 μg/mL.109 A genome-wide transcription analysis revealed that the antibiotic effects involved multiple novel cellular targets governing cell division resulting in destabilization of the bacterial cell membrane, suppression of protein synthesis, and inhibition of cell growth that led to cell death. This novel approach to inactivation of resistant bacteria merits further exploration. Tomatidine. Hydrolytic removal of the tetrasaccharide side chain from the tomato glycoalkaloid α-tomatine results in the formation of the aglycone tomatidine.110 Although inactive alone, tomatidine specifically enhances the inhibition of MRSA by aminoglycoside antibiotics by blocking the expression of several genes in the resistant bacteria,111 suggesting that tomatidine is an aminoglycoside potentiator that acts as an antivirulence agent targeting both susceptible and resistant S. aureus. It would be of interest to find out whether the aglycones tomatidenol and solanidine derived from the tomato glycoalkaloid dehydrotomatine and potato glycoalkaloids αchaconine and α-solanine, respectively,112 would also enhance inhibition of MRSA.

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PLANT EXTRACTS AS ANTIMICROBIALS Essential Oils and Oil Compounds. We published a series of studies on the inactivation in vitro and in food of individual and multiple foodborne pathogens by plant essential oils and some of their bioactive compounds.9,10,113−121 The following observations indicate that plant essential oils and some of their bioactive compounds are also strong inhibitors of resistant bacteria, reviewed by Yap et al.7 An evaluation of the bioactivity of oregano oil, carvacrol, and thymol against methicillin-susceptible and -resistant Staphylococci by Nostro et al.122 showed that all three substances inhibited both types of pathogens to the same extent, with MIC values for carvacrol of 0.015−0.03%. The essential oil from the Korean Thymus plant and its components carvacrol and thymol inhibited both susceptible and resistant strains of Streptococcus E



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pneumoniae, S. aureus, Salmonella Enteritidis, and Salmonella Typhimurium with MIC values ranging from 0.125 to 8 mg/ mL.123 Carvacrol and thymol were highly effective in reducing the resistance of microbes, including Salmonella and E. coli, to several antibiotics; some combinations of the plant and medical antibiotics acted synergistically, suggesting that natural antibiotics can decrease the MIC of a diverse group of drugresistant bacteria.124 Subinhibitory concentrations of five natural antimicrobials including carvacrol individually and synergistically increased the susceptibility of resistant Salmonella Typhimurium to five medical antibiotics, suggesting the potential value of the natural compounds as feed supplements to reduce the resistance of Salmonella in food animals.91 Carvacrol and cinnamaldehyde rapidly inactivated susceptible and resistant Campylobacter jejuni strains, suggesting that the same mechanism probably governs the inactivation of both types of pathogens.125 These two compounds also inhibited resistant Campylobacter on chicken breast126 and resistant S. enterica on celery and oysters,127 suggesting that these plant antimicrobials have the potential to be used to decontaminate resistant pathogens on seafood, salads, and oysters. Carvacrol, cinnamaldehyde, and eugenol decreased a five-strain mixture of nalidixic acid-resistant Salmonella on shell eggs from log 8.0 log CFU/mL to undetectable levels, suggesting that the natural antimicrobials could be used as a wash treatment to reduce Salmonella Enteritidis on shell eggs.128 Our studies also indicate that the antimicrobial efficacy of carvacrol is similar to that of oregano oil with a ∼80% carvacrol content, suggesting that the minor components do not seem to contribute to the bioactivity.9,129 Tea tree oil (Melaleuca alternifolia) was shown to be effective as an adjunctive therapy in treating osteomyelitis and infected chronic wounds in human case studies and small clinical trials.130 Other studies showed that tea tree oil did not induce bacterial resistance to antimicrobial agents, including carvacrol,131 and that Thymus maroccanus essential oil and its major components carvacrol and thymol modified the susceptibility of resistant bacteria to antibiotics by a membrane-associated mechanism, thereby conferring antibiotic resistance to bacteria.132 A follow-up study found that the oil can restore antibiotic activities of resistant Gram-negative bacteria by blocking the antibiotic efflux through inhibition of the functional assembly of the efflux pump component.133 Extracts of the Brazilian medicinal plant Lippia origanoides, containing about 20 compounds including carvacrol and thymol, potentiated the action of neomycin and amikacin against MRSA in vitro, suggesting that the plant could be a source of secondary metabolites for use in antibiotic chemotherapy of MRSA-caused infections.134 In addition, a Korean study found that essential oils from two Thymus magnus plants and their bioactive constituents, carvacrol and thymol, restored the activity of several Salmonella and S. aureus bacteria to the quinolone antibiotic norfloxacin.123 As already mentioned, combinations of extracts or natural products, whether with other natural products or conventional antibiotics, can have a synergistic effect. For example, carvacrol in combination with methyl gallate isolated from Galla rhois exhibited enhanced activity against eight nalidixic acid-resistant pathogenic bacteria compared with the activities observed with the individual compounds.135 These results indicate that carvacrol and methyl gallate alone or in combination have potential use against nalidixic acid-resistant bacteria. It was also reported that carvacrol, cinnamaldehyde, cinnamic acid, and

eugenol in combination with antibiotics acted synergistically against 39 pathogenic microorganisms,136 and cinnamon bark, lavender, and peppermint essential oils evaluated against E. coli reduced the resistance to several antibiotics, suggesting the possibility of their use to reverse β-lactam antibiotic resistance and potentially resulting in a reduced use of antibiotics.137 Carvacrol and thymol have also been tested against fungal pathogens and were shown to synergistically enhance the efficacy of the antifungal drug fluoconazole against resistant pathogenic C. albicans isolates by chemosensitizing the fungal cells to the drug and decreasing its efflux, suggesting their value in therapy for candidiasis.138 Essential oil components have also been tested for their use in animal feeds. For example, an in vitro study demonstrated the efficacy of essential oil compounds (carvacrol, thymol, linalool, nerolidol, cinnamaldehyde, eugenol, piperine, and capsaicin) to inhibit susceptible and resistant Brachyspira intermedia, the cause of intestinal spirochetosis in hens. Consumption of feed supplemented with coated transcinnamaldehyde cured the hens of the disease.139 Garlic Extracts. An evaluation of an ethanol garlic extract against 15 MDR and 5 non-MDR clinical isolates of Mycobacterium tuberculosis showed that the extract inhibited both types of isolates, with MIC values ranging from 1 to 3 mg/ mL.140 The authors suggest that garlic extracts have the potential to prevent/treat MDR tuberculosis. In another study, an evaluation of the inhibitory activity of a garlic (Allium sativum) extract against MDR strains of Streptococcus mutans isolated from human carious teeth using disc sensitivity and broth dilution methods showed that (a) of 105 carious teeth tested, 92 (87.6%) isolates of S. mutans were recovered; (b) 28 (30.4%) were resistant to four or more antibiotics; and (c) all MDR and non-MDR isolates were susceptible to the garlic extract with MICs ranging from 4 to 32 μg/mL. These results suggest that mouthwashes or toothpaste containing the garlic extract have the potential to prevent human dental caries and possibly also infectious diseases originating from tooth decay.141 Organic Herbal Products. An evaluation of resistance in six pathogens from herbal products grown organically and conventionally (garlic, ginger, goldenseal, mustard, onions) revealed the prevalence of low resistance, suggesting that organic farming could contribute to reduced resistance in foodborne bacteria.30 It is not immediately apparent why organic food might contain low levels of resistant bacteria. One possible explanation is that, to protect themselves against phytopathogens in the absence of pesticides, organic plants produce greater amounts of bioactive secondary metabolites than do conventionally grown plants. Honey and Propolis. The commercial honey preparation MEDIHONEY has been approved by the FDA as an antimicrobial to help heal traumatic wounds. MEDIHONEY was shown to inhibit the resistant Gram-negative bacterium A. baumanii and also MRSA in vitro with MIC values of 8.5 and 3.5%, respectively,142 whereas “supermarket honey” induced bacterial and fungal growth. Related studies found that MEDIHONEY in combination with the antibiotic rifamycin acted synergistically against MRSA and clinical isolates of S. aureus, suggesting that the combination may be an effective therapy for chronic wound infections.142,143 The bee product propolis, a resinous mixture, has also been reported to have antimicrobial properties. Indeed, ethanol extracts of the bee F



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products propolis and honey acted synergistically against resistant S. aureus and E. coli, as well as against the fungus C. albicans, suggesting the need to isolate the active antimicrobial ingredients from propolis and honey.144 Three possible antimicrobial ingredients have been identified in honey, hydrogen peroxide, methylglyoxal, and the peptide defensin-1, and the low pH of honey may contribute to its activity.145 Mushroom Extracts. Purified phenolic compounds derived from mushrooms have been tested for their antibacterial activity against resistant strains. In addition, whole extracts have been used against clinical bacterial strains. For example, an ethyl acetate extract of the culture filtrate and fruiting bodies of the mushroom Xylaria showed significant antimicrobial activity against clinical MDR S. aureus and Pseudomonas aeruginosa strains, with MIC values (in μg/mL) of 225−625 and 120− 625, respectively, suggesting that Xylaria mushrooms are a potential source of new antimicrobial compounds.146 Pepper Extracts. An investigation into edible pepper (Piper nigrum) and, in addition, the tropical vine Telfairia occidentalis plant extracts showed they were active against 29 pathogenic microorganisms in the absence and presence of the efflux pump inhibitor (EPI) phenylalanine-arginine-β-naphthylamide (PAβN), suggesting that these extracts may help control bacterial infection including MDR phenotypes.147 Nanoliposomes containing the pepper compound piperine and the antibiotic gentamycin were effective against MRSA, with MIC values of 100 and 32 μg/mL, respectively.148 Pomegranate Extracts. Methanolic extracts of the pomegranate (Punica granatum) fruit pericarp acted synergistically with the antibiotic ciprofloxacin against resistant strains of E. coli, Klebsiella pneumoniae, and P. aeruginosa, suggesting that the observed synergy against ESBL- and MBL-producing Gram-negative bacteria may help provide an inexpensive alternative therapy against resistant pathogens.149 Red Cabbage Extracts. Methanol extracts of red cabbage exhibited antimicrobial activity against MDR bacteria that were resistant to 15 antibiotics as well as against human fungal pathogens.150 The antimicrobial effects are probably due to the high anthocyanin content. Safe cabbage extracts merit evaluation for efficacy against in vivo infections. Teas Extracts, Tea Catechins, and Theaflavins. We previously reported that commercial teas and their bioactive constituents, catechin and theaflavin, strongly inhibited susceptible Bacillus cereus bacteria and that the antimicrobial activity of a large number of teas correlated with their composition as determined by HPLC.151 The antimicrobial efficacies of the teas correlated with their flavonoid contents determined by HPLC.152 Table 2 illustrates the exceptional activity of freshly prepared teas and tea compounds against this pathogen at nanogram levels, suggesting that the mentioned pure black and green tea flavonoids might merit further study for their potential to inhibit resistant pathogens. Other investigators reported that tea compounds also inhibited resistant bacteria. For example, aqueous extracts of Japanese green tea (Camellia sinensis) and the epigallocatechin gallate (ECGC) component inhibited oxacillin β-lactam resistance in MRSA. The tea polyphenolic compounds reduced the MIC values several hundred-fold.153 These results indicate that teas and their bioactive compounds can inhibit both susceptible and resistant pathogens. Long-term storage of teas seems to degrade some of their bioactive compounds.154 Yerba mate tea, an infusion made from the leaves of the tree Ilex paraguariensis, is a widely consumed nonalcoholic beverage in

Table 2. Bactericidal Activity of Tea Flavonoids Compared to Medicinal Antibiotics against Bacillus cereus, Where BA50 Equals Percent Concentration That Killed 50% of the Bacteria (Lower Number = Greater Activity151) compound (−)-gallocatechin-3gallate theaflavin-3,3′-digallate (−)-epigallocatechin-3gallate theaflavin-3′-gallate rifampicin vancomycin HCl theaflavin-3-gallate (−)-catechin-3-gallate tetracycline HCl clindamycin (−)-epicatechin-3gallate gentamycin sulfate chloramphenicol theaflavin (−)-epigallocatechin (−)-gallocatechin (GC)

BA50 (nmol/well)

relative activities to least active compound, (−)-GC

0.43

2307

0.54 0.68

1837 1459

1.8 2.1 2.3 2.8 5.5 12 19 22 75 180 283 800 992

551 472 431 354 180 83 52 45 13 5.5 3.5 1.2 1.0

South America.155 Burris et al.156 found that low concentrations of the tea inhibited MSRA in culture and in beef.

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OTHER METHODS OF TREATING RESISTANT BACTERIA It is worth mentioning here some of the other more biological and physical methods for combatting bacterial resistance, techniques that could perhaps be used in combination with some of the strategies described above. Bacteriophages. Immersion of live oysters contaminated with the virulent multiple-antibiotic-resistant Vibrio parahemolyticus bacteria in a bacteriophage-containing bath induced a significant reduction in the growth of the pathogens, suggesting the potential use of the phage to avoid infection from aquaculture to consumption.157 As noted above, carvacrol and thymol inactivated resistant S. enterica on contaminated oysters.127 Will adding these antimicrobials to oyster-containing water tanks reduce microbial contamination? Chlorine Disinfection. A chlorine dose of 100 mg/L effectively achieved complete removal of susceptible and resistant pathogens in various sites of two anaerobic swine wastewater systems, one anaerobic and the other aerobic.158 The authors also report that ammonia present in the system can compete with chlorine to form monochloramine and that aeration helps remove ammonia, thus improving the efficacy of chlorine in overcoming antibiotic pollution. A related study159 found that inactivation of both susceptible and resistant Salmonella Typhimurium in chlorinated water displayed nonlinear kinetics with a concave downward curve (R2 = 0.964) that fit the power law model, with a shape parameter of 1.37. In addition, the D value for a single log reduction from an initial concentration of 5.36 log CFU/mL did not differ among the four resistant groups evaluated and ranged from 3.8 to 4.3 min,159 suggesting that the resistance phenotype does not impart cross-protection to chlorine inactivation in chilled water. Thermal Inactivation. An evaluation of the effect of temperature (55−70 °C) on 10 MDR and 10 non-multidrugG



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Table 3. Summary of Antiresistant Formulations Described in the Text pure compound

resistant pathogens inhibited

baicalein aminocoumarins anchovy peptide capsaicin carnosic acid catechins and theaflavins, tea carvacrol chlorogenic acid cinnamaldehyde citral cinnamic acid curcumin dopamine ferulic acid gallic acid iberin ellagitannins enterocin gallotannin eugenol indolecarbinol linalool methyl gallate milk protein, human nerolidol piperine perillaldehyde plumbagin rosmarinic acid β-resorcylic acid

S. aureus, L. monocytogenes S. aureus B. cereus, E. coli, Salmonella Typhi, S. aureus B. intermedia Campylobacter strains, E. faecalis, S. aureus L. monocytogenes, S. aureus B. cereus, E. coli, S. aureus, C. albicans Campylobacter strains, S. aureus B. cereus, B. intermedia, E. coli, S. aureus E. coli M. tuberculosis enhanced resistance response in Salmonella B. cereus, E. coli, S. aureus Campylobacter strains Campylobacter strains P. aeruginosa S. aureus S. aureus E. coli B. cereus, E. coli, S. aureus Gram-negative bacteria B. intermedia multiple resistant bacteria A. baumanii, Moraxella catarrhalis B. cereus, B. intermedia, E. coli, S. aureus B. intermedia, S. aureus B. cereus, E. coli, S. aureus E. coli Campylobacter strains B. cereus, E. coli, S. aureus

pure compound sinapinic acid shiknin syringic acid tannic acid thymol tomatidine triterpenoids vanillic acid plant extracts cabbage garlic horseradish mushrooms Lippia origanoides medicinal plant pepper pomegranate Yerba mate tea others bacterial quorum sensing bacterial SOS response bacteriophage chlorine essential oils heat honey, propolis hydrostatic pressure pulsed electric fields UV light

resistant (NMDR) Salmonella strains isolated from cattle or cattle environments found that NMDR serotypes had a slightly higher heat resistance than MDR serotypes.160 Salmonella Agona and Salmonella Anatum serotypes had the highest resistance. The Salmonella Agona serotype survived in ground beef patties cooked to an internal temperature of 71 °C. The authors conclude that drug resistance does not seem to affect the heat resistance of Salmonella and that serotype or strain is an important consideration in risk assessment of the pathogen’s survival at cooking temperatures. A related study evaluated the inactivation of rifampicinresistant E. coli O157:H7 in pan-broiled or roasted beef at different temperatures.161 The highest reduction of 5.5 log CFU/g was obtained in samples cooked in the kitchen oven set at 260 °C. The authors suggest that the observed results could facilitate the use of cooking methods to enhance the safety of beef products. Pulsed Electric Fields (PEF). Repeated rounds of PEF treatment and outgrowth of survivors of Salmonella enterica serovar Typhimurium SL1344 resulted in a culture that showed higher resistance to PEF.162 Additional studies showed that (a) the membranes of the resistant organisms were less susceptible to permeabilization (disruption) than those of the parental strain and (b) resistance to PEF was accompanied by higher tolerance to acidic pH, hydrogen peroxide, and ethanol, but not to heat. The authors suggest the need to study the mechanism of PEF resistance. UV Disinfection. A Chinese study found that the exposure of resistant bacteria in reclaimed wastewater to UV light

resistant pathogens inhibited Campylobacter strains E. coli Campylobacter strains E. coli B. cereus, B. intermedia, E. coli, S. aureus, C. albicans S. aureus S. aureus Campylobacter strains multiple MDR bacteria M. tuberculosis P. aeruginosa Campylobacter, S. aureus, P. aeruginosa E. coli multiple resistant phenotypes E. coli, K. pneumoniae, P. aeruginosa S. aureus Salmonella strains E. coli V. parahemolyticus multiple pathogens Campylobacter, E. coli, S. aureus, S. pneumoniae E. coli, Salmonella A. baumanii, E. coli, S. aureus E. coli, Salmonella Salmonella E. coli, Listeria

resulted in a 4 log CFU reduction of total heterotrophic bacteria. After a standing incubation for 22 h, however, the resistant bacteria mostly reactivated.163 Related observations indicate that (a) exposure of E. coli in wastewater to solar and UV light in the presence of the photocatalyst TiO2 for 30−60 min inactivated the organisms and that an antibiotic resistant test (Kirby−Bauer) on surviving colonies showed that the photocatalytic process affected the resistance of the strains to the target antibiotics differently;164 and (b) acid-stressed resistant strains of Listeria monocytogenes were more resistant to disinfection in distilled water and a 9% sodium chloride solution by UV light than were unstressed and heat-resistant and heat-shocked strains.165 Hydrostatic Pressure. High-pressure processing of green onions inoculated with resistant Salmonella and E. coli O157:H7 to an average of 5−6 log CFU/g reduced the bacteria by 0.6−5 log CFU/g, depending on the pressure level and sample wetness state.166 Because the pressure treatment had a minimal adverse effect on most sensory properties and color, it seems that hydrostatic pressure offers an approach to reduce the risk of consumption of contaminated onions. The application of pressure to inactivate resistant pathogens merits further study.167 Table 3 summarizes this section, showing the antimicrobial formulations and the respective resistant pathogens inhibited. Bacterial Resistance Mechanisms. In their review on bacterial multidrug efflux pumps that govern the resistance of bacterial pathogens, Sun et al.168 note that MDR refers to the capability of bacterial pathogens to withstand lethal doses of H



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acid metabolism and repair, or protein synthesis, and the fourth involves the disruption of membrane structure. To combat resistance there are, however, some more unusual modes of action that could hinder the evolution of resistance, involving the disruption of bacterial quorum sensing or the bacterial SOS response. Bacterial Quorum Sensing (QS) Inhibition. Instead of killing the bacteria, interruption of bacterial communication by QS, where individual cells release small signal molecules such N-acylhomoserine lactone (AHL), might also benefit microbial food safety.177 To demonstrate this possibility, the cited authors determined the inhibition of QS in the opportunistic pathogen Pseudomonas aeruginosa by the horseradish (Armoracia rusticana) compound iberin. Real-time PCR (RT-PCR) and DNA microarray studies showed that iberin blocked the expression of the QS-regulated genes LasIR and RhIIR and downgraded QS-controlled rhamnolipid production in wildtype cultures of the bacterium, suggesting the need for an epidemiological study of the relationship between the ingestion of food known to contain QS inhibitors (such as cabbage, garlic, and horseradish) and the incidence/severity of bacterial infections. In a related study, trans-cinnamaldehyde and tannic and salicylic acids strongly inhibited AHL synthase in E. coli,178 suggesting that the inhibition of the enzyme by natural products may facilitate the discovery of novel anti-infectives based on anti-QS mechanisms. The results of another study demonstrated that cinnamon bark or lavender essential oils, acting as apparent QS inhibitors, individually and in combination with the antibiotic piperacillin, reduced bioluminescence expression in resistant E. coli, suggesting that the oils have the potential to reverse resistance to piperacillin in the bacteria via two mechanisms, alteration of the outer membrane permeability and inhibition of bacterial QS as a novel approach to reverse resistance.179,180 A review by Koh et al.181 discusses the use of autoinducers such as AHL to regulate the formation and release of virulence factors, biofilm formation, antibiotic production, the potential of numerous plant-derived products to inhibit QS, and the need to explore the synergistic effects of anti-QS antagonists and antibiotics and concludes that anti-QS is as important as antibacterial activity as it is not likely to cause resistance because it does not pose selection pressure. Bacterial SOS Response Inhibition. Exposure of bacteria to stress (heat, pH, UV light, disinfectants, antimicrobials) may induce a so-called SOS response that facilitates their survival and that may result in the induction of genetic diversity, formation of reactive oxygen species (ROS), formation of biofilms, and stress-resistant subpopulations.182,183 The biphasic kinetics of heat and antimicrobial destruction of bacteria in a ground beef matrix described by Juneja et al.184,185 support the possible significance of the SOS response in microbial foods safety. Other studies have also provided support for the importance of the SOS response. For example, aminocoumarins strongly inhibited fluoroquinolone-induced RecA genes and the SOS response (resistance development) in S. aureus, suggesting that the combination could be useful in anti-infective therapy.186−188 In addition, baicalein, a flavone present in Scutellariae baicalensis radix (described above),189 was found to be a potent inhibitor of the expression rifamycinresistant genes and ROS and ATP levels in S. aureus, suggesting that it may be used to prevent mutations induced by antibiotics.95 By contrast, the food ingredient curcumin

drugs that are capable of eradicating nonresistant strains and that among the four general mechanisms that cause resistance (target alteration, drug inactivation, decreased permeability, and increased efflux), drug extrusion serves as an important mechanism of MDR. An understanding of the mechanism of extrusion is therefore of importance for the development of antiresistant interventions.169,170 We will now briefly summarize some of the reported mechanisms that may govern resistant activities of several natural antimicrobials. A study of the resistance mechanisms of phenolic compounds [(−)-epigallocatechin gallate and carnosic, chlorogenic, ferulic, gallic, rosmarinic, sinapinic, syringic, and vanillic acids] in resistant Campylobacter strains in the absence and presence of EPIs showed that (a) inactivation of the cmeB efflux gene rendered the bacteria more susceptible to the phenolic compounds; (b) mutations of the cmeF efflux and cmeR transcriptional repressor genes produced a moderate effect on the MICs; and (c) efflux pump inhibitors significantly reduced the MICs of the antimicrobials, suggesting that the antiresistant compounds can be developed for use in live poultry or processed meat to reduce transmission of the pathogens to humans.171 Three pure plant compounds (plumbagin from Plumbago indica, nordihydroguaretic acid from creosote bush, and shikonin from Lithspermum erythrorhizon) were able to inhibit substrate efflux from resistant pathogenic E. coli cells that is mediated by the multidrug efflux pump AcrB, suggesting that the gene docking used to predict the bioactivity could be used to preselect compounds with potential EPI activity.172,173 A study with indole-3-carbinol, a natural compound found in the edible plant family Cruciferae, found that the antimicrobial activity against Gram-negative bacteria was influenced more by the barrier action of the outer cell membrane lipopolysaccharide than by the action of efflux pumps. It was also found that the compound acted synergistically with ampicillin against drug-resistant isolates, possibly by the facilitated entry of the carbinol after the partial disruption of the cell wall by the antibiotic.174 The activity of the natural compound carnosic acid on the uptake/efflux of ethidium bromide is correlated with its ability to change the membrane potential gradient in S. aureus and E. faecalis, suggesting that the acid can function as an efflux pump modulator that can be used in combination therapies against resistant Enterococci and S. aureus.175 A study of the ability of the essential oil of Thymus riartarum to block efflux pump systems of six resistant Gram-negative bacteria showed that (a) the antimicrobial activity of the oil was significantly enhanced by the efflux pump inhibitor PAβN and (b) the oils also enhanced the susceptibility of resistant isolates to the antibiotic chloramphenicol, suggesting that it could be a candidate for a new drug that can restore the antimicrobial activity of antibiotics by chemosensitive and membranotropic effects.176 Collectively, the cited studies indicate that natural, foodcompatible compounds have the potential to help overcome the resistance of antibiotics, an approach that merits further investigation.

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STRATEGIES FOR COMBATTING BACTERIAL RESISTANCE Conventional antibacterial actions can generally be divided into four mechanisms, three of which involve the inhibition or regulation of enzymes involved in cell wall biosynthesis, nucleic I



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enhanced the ciprofloxacin-induced SOS response in Salmonella Typhimurium and Salmonella Typhi, thus significantly enhancing Salmonella pathogenesis.190 Whether the SOS response can induce/prevent resistance in different antimicrobials merits further study. More Conventional Mechanisms of Action. The section on mechanisms of resistance discussed some of the methods by which the compounds overcome the main mechanism of drug extrusion. Here, some of the experimental approaches designed to define the mechanisms that might govern the antimicrobial effects of some of the compounds and extracts described above are briefly mentioned. Most of the methods and mechanisms focused on here involve effects on the bacterial membrane. Bacterial Membrane Disruption. Exposure of B. cereus to carvacrol results in the depletion of the intracellular ATP pool, a change in membrane potential, and an increase in the permeability of the cytoplasmic membrane for protons and potassium ions.191 The loss of the ion gradient impairs essential metabolic processes in the cell and consequently leads to cell death. We have used the technique of autofluorescence spectra to determine the effect of carvacrol on another pathogen, E. coli.129 The autofluorescence spectra and data showed significant changes at much lower concentrations of carvacrol (0.01 mM) than changes in membrane potential or release of ATP (ATP flux) after disruption of the bacterial cell membrane (1−2 mM), suggesting that autofluorescence detects physiological responses to carvacrol more efficiently than do changes in membrane potential or release of ATP. We have also used molecular dynamics simulations to study the interactions of green tea catechins and black tea theaflavins with the lipid bilayer of artificial biological membranes.192−194 The results showed that both catechins and theaflavins have a strong affinity for the lipid bilayer of the cell membranes via hydrogen bonding to the surface, with some able to penetrate underneath the surface. In addition, the molecular structure of the tea compounds influenced their configuration when binding to the bilayer surface, as well as their ability to form hydrogen bonds with the lipid headgroups. These studies help to define structure−function relationships and provide a better understanding of the antimicrobial mechanisms of the tea compounds at the molecular−cellular levels. Computer simulation methods can also be used to predict the antimicrobial and anticarcinogenic properties of natural bioactive compounds.195−197 Another study used a Langmuir trough equipped with a computer-controlled microbalance to measure the effect of carvacrol and four other natural antimicrobials on monolayers of model membranes composed of bacterial phospholipids.198 Surface pressure−area (π−A) and surface potential−area (Δψ− A) isotherms were measured to monitor changes in the thermodynamic and physical properties of the lipid monolayers. Carvacrol modified the three lipid monolayer structures by integrating into the monolayer, forming aggregates of antimicrobial−lipid complexes, reducing the packing effectiveness of the lipids, increasing the membrane fluidity, and altering the total dipole moment in the monolayer membrane model. It has been reported that exposure of B. cereus to subinhibitory, nonlethal concentrations of carvacrol resulted in increased resistance of the bacteria to inhibition that was accompanied by a lowering of membrane fluidity associated with changes in their fatty acid and headgroup composition.199 Similar changes in membrane fatty acid profiles observed by Di Pasqua et al.200 and by Luz Ida et al.201 suggest that the

mechanism of the antimicrobial effect is associated with an alteration in membrane lipid profiles and damage to the cell envelope. Some constituents of essential oils including carvacrol were analyzed for their mechanism of action against a range of pathogens using a novel whole-cell biosensor assay. The results suggest that the antimicrobial mechanism of action of carvacrol and related compounds involves damage to cell membranes and disruption to cellular metabolism and energy production.202 Another set of studies examined the combination of carvacrol and low doses of γ-radiation against B. cereus. Various techniques were used to monitor the effects, and it was demonstrated that the combination synergistically inhibited B. cereus via disruption of cell membranes, with the combination being more effective than either treatment alone, suggesting that the treatment could be effective in contaminated food.203,204 Many other studies have indicated the involvement of membrane disruption in the mechanism of action of some natural products. For example, cinnamaldehyde at MIC induces cell death of E. coli and S. aureus that results from the lysis of the cell membrane;205 the antimicrobial activity of a peptide from anchovy (Engraulis japonicus) seems to be associated with the disruption of membranes of B. cereus, E. coli, Salmonella Typhi, and S. aureus;206 and an increase in resistance in E. coli strains stimulated by Thymus maroccanus essential oil was associated with changes in the composition of the microbial membrane, suggesting an adaptation or stimulation of the native resistance to the components of the natural oil.132 The tea polyphenol (−)-epicatechin gallate (ECG) disrupts the secretion of virulent coagulase and α-toxin by Staphylococcus aureus,207 suggesting action via disruption of the cytoplasmic membrane. Components of pomegranate rind were analyzed to investigate their antibacterial mode of action. The results indicate that the phenolic pomegranate compounds act by impairing the membrane structure of L. monocytogenes, suggesting their potential as food preservatives and in the reduction of listeriosis.208 Bacterial membrane disruptive proteins have been widely reported as promising targets for potential antibacterial therapy, and a greater understanding of the composition and function of the complexes they form could aid antibiotic development.132,209,210 DNA Interactions and Other Mechanisms. Many modes of action are not at all well-defined or compounds may have multiple modes of action. For example, in a study on the effects of carvacrol and thymol on bacteria and fungi, it was reported that they induced their antimicrobial activity via a mechanism that involves the production of formaldehyde and its reaction products.211 Carvacrol and thymol have also been shown to bind to DNA via H-bonding of the OH group to the guanine N7, cytosine N3, and backbone phosphate group, with binding constants of K = 1.55 × 103/M and 2.43 × 103/M, respectively, suggesting that the mechanism of formation of the DNA complexes can serve as a model for drug−DNA interactions.212 The antibacterial activity of the wine compound resveratrol seems to result from the induction of cellular stress and not from direct membrane perturbation.213 The mechanism of action of essential oil components has been shown to be complex, possibly involving different mechanisms depending on the conditions. Indeed, cell death in E. coli caused by citral and carvacrol has been reported to be J



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whether or not the resistant activities observed in vitro can be duplicated in vivo, especially in humans. Another area concerning efficacy and safety that would be of interest for investigation is whether resistant formulations can also inhibit endotoxemias associated with human pathogens218,219 and determining whether or not resistant pathogens release toxins to the same extent as susceptible pathogens.220 As discussed in this paper, many of the natural antimicrobials have additive and synergistic effects in combination with medicinal antibiotics, and these synergisitic effects merit further study in vivo. The same applies for their use as food additives. For example, it would be interesting to determine whether or not combinations of resistant food ingredients that act synergistically will be safer and will affect less the color, flavor, and taste of food than the individual compounds.221 When considering their application as food additives, previous studies have investigated the use of certain natural products to reduce concurrently both resistant pathogens and carcinogenic heterocyclic amines in cooked meat.119,222,223 Such investigations merit further study. It would be interesting to know if the consumption of compounds elicits a lower risk of infection and cancer in humans. Some natural products that are inhibitors of bacterial resistance also have other beneficial properties. For example, carvacrol has analgesic, antiarthritic, antiallergic, anticarcinogenic, antidiabetic, cardioprotective, gastroprotective, hepatoprotective, and neuroprotective properties as well.11 It would therefore be of interest to investigate any additional medicinal properties of the other food-compatible compounds and extracts described here. We are challenged to help solve these problems associated with microbial food safety and human health.

associated with oxidative DNA damage, suggesting their possible value as alternative antimicrobials.214 Free fatty acids have antibacterial properties, and although their main target of action is the cell membrane, their mode of action is diverse, and they are less likely to induce resistance than conventional antibiotics, suggesting their potential for commercial use.215 The cited results provide insights into the mechanisms of the molecular interactions between naturally occurring antimicrobial compounds and, in most cases, the phospholipids of the bacterial cell membrane that govern activities. As described, the mechanisms can be complex, however, and are still not yet fully elucidated. Moroever, similar mechanisms might govern membrane disruption of susceptible and resistant pathogens by natural antimicrobials. A better understanding of the mechanisms that govern the antimicrobial activities of natural compounds will help in the design of approaches to inhibit resistant bacteria in different environments. It is largely not known whether the use of many of the natural antimicrobials will result in the development of resistance associated with standard antibiotics.

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OUTLOOK AND AREAS FOR FUTURE RESEARCH Antibiotic resistance often arises from the administration of subtherapeutic levels of antibiotics in animal feeds. Resistant microorganisms may be present in the animal waste, contaminating ground, surface, and irrigation waters and often contaminating fruits, vegetables, and other edible plant tissues. They suffuse throughout the food chain and can enter the human intestinal tract after the produce or the undercooked meat, poultry, and other food products are consumed. There is, therefore, a need to develop new alternatives to standard antibiotics, preferably based on safe, food-compatible plant compounds and extracts that can be effective against both susceptible and resistant bacteria. It is hoped that the present overview of multidisciplinary aspects of antibiotic resistance and its prevention will help meet this need. Largely unanswered questions are whether or not different classes of natural antimicrobials that have been found to be effective against susceptible pathogens will exhibit similar efficacy against resistant bacteria and fungi and whether antimicrobial activities in vitro will be duplicated in vivo after consumption by foodproducing animals and by humans. There are many areas in which further studies could help to address some specific aspects of antiresistance. For example, from a mechanistic point of view, it would be useful to devise strategies to bypass the bacterial membrane barrier comprising influx and efflux mechanisms to restore the activity of antibiotics against resistant bacteria,216 and determine the relative potencies of structurally different efflux pump inhibitors in resistant pathogens.175,217 With regard to the whole food chain, it would be useful to investigate the efficacy of natural antimicrobials as a replacement for antibiotics in animal feed, where antibiotic resistance can arise. As indicated above, there may be differences in the prevalence of resistance between organic and conventional produce. It would be interesting to compare the prevalence of resistant bacteria in various conventional and organic foodstuffs. The efficacy of many of these compounds is not known in vivo, and safety is paramount. Thus, the bioavailability, metabolism, and safety of antimicrobial compounds in animals and humans remains to be investigated further, and as does

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AUTHOR INFORMATION

Corresponding Author

*Phone: (510) 559-5615. E-mail: [email protected]. gov. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

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ABBREVIATIONS USED

I thank my colleagues whose names are shown in the cited references for excellent collaboration and Carol E. Levin for facilitating the preparation of the manuscript.

AGP, antimicrobial growth promoters; AHL, N-acylhomoserine lactone; AR, antibiotic resistance; AS, antibiotic-sensitive; CFU, colony-forming units; D value, time in minutes to kill 90% of the bacteria or 1 log reduction; EPI, efflux pump inhibitor; ESBL, extended spectrum beta-lactamase; MAR, antibioticresistant mutants; MDR, multidrug resistant; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; NMDR, non-multidrug-resistant; PAβN, phenylalanine-arginine-β-naphthylamide resistant inhibitor; PEF, pulsed electric field; QS, quorum sensing; QSAR, quantitative structure−activity relationship; ROS, reactive oxygen species; RTE, ready-to-eat; VRE, vancomycin-resistant Enterococci; VTE, verocytotoxigenic bacteria K



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(19) Fluckey, W. M.; Loneragan, G. H.; Warner, R.; Brashears, M. M. Antimicrobial drug resistance of Salmonella and Escherichia coli isolates from cattle feces, hides, and carcasses. J. Food Prot. 2007, 70, 551−556 http://www.ingentaconnect.com/content/iafp/jfp/2007/00000070/ 00000003/art00003. (20) Gomes-Neves, E.; Antunes, P.; Manageiro, V.; Gärtner, F.; Caniça, M.; da Costa, J. M. C.; Peixe, L. Clinically relevant multidrug resistant Salmonella enterica in swine and meat handlers at the abattoir. Vet. Microbiol. 2014, 168, 229−233. (21) Mathew, A. G.; Cissell, R.; Liamthong, S. Antibiotic resistance in bacteria associated with food animals: a United States perspective of livestock production. Foodborne Pathog. Dis. 2007, 4, 115−133. (22) Zhang, L.; Huang, Y.; Zhou, Y.; Buckley, T.; Wang, H. H. Antibiotic administration routes significantly influence the levels of antibiotic resistance in gut microbiota. Antimicrob. Agents Chemother. 2013, 57, 3659−3666. (23) Gorski, L.; Jay-Russell, M. T.; Liang, A. S.; Walker, S.; Bengson, Y.; Govoni, J.; Mandrell, R. E. Diversity of pulsed-field gel electrophoresis pulsotypes, serovars, and antibiotic resistance among Salmonella isolates from wild amphibians and reptiles in the California Central Coast. Foodborne Pathog. Dis. 2013, 10, 540−548. (24) Carroll, D.; Wang, J.; Fanning, S.; McMahon, B. J. Antimicrobial resistance in wildlife: implications for public health. Zoonoses Public Health 2015, DOI: 10.1111/zph.12182. (25) Jay-Russell, M. T.; Hake, A. F.; Bengson, Y.; Thiptara, A.; Nguyen, T. Prevalence and characterization of Escherichia coli and Salmonella strains isolated from stray dog and coyote feces in a major leafy greens production region at the United States-Mexico border. PLoS One 2014, 9, article e113433 10.1371/journal.pone.0113433 (26) Park, S.; Szonyi, B.; Gautam, R.; Nightingale, K.; Anciso, J.; Ivanek, R. Risk factors for microbial contamination in fruits and vegetables at the preharvest level: a systematic review. J. Food Prot. 2012, 75, 2055−2081. (27) Oliveira, M.; Viñas, I.; Usall, J.; Anguera, M.; Abadias, M. Presence and survival of Escherichia coli O157:H7 on lettuce leaves and in soil treated with contaminated compost and irrigation water. Int. J. Food Microbiol. 2012, 156, 133−140. (28) Mootian, G.; Wu, W. H.; Matthews, K. R. Transfer of Escherichia coli O157:H7 from soil, water, and manure contaminated with low numbers of the pathogen to lettuce plants. J. Food Prot. 2009, 72, 2308−2312 http://www.ingentaconnect.com/content/iafp/jfp/2009/ 00000072/00000011/art00010. (29) Holvoet, K.; Sampers, I.; Callens, B.; Dewulf, J.; Uyttendaele, M. Moderate prevalence of antimicrobial resistance in Escherichia coli isolates from lettuce, irrigation water, and soil. Appl. Environ. Microbiol. 2013, 79, 6677−6683. (30) Brown, J. C.; Jiang, X. Prevalence of antibiotic-resistant bacteria in herbal products. J. Food Prot. 2008, 71, 1486−1490 http://www. ingentaconnect.com/content/iafp/jfp/2008/00000071/00000007/ art00025. (31) Micallef, S. A.; Goldstein, R. E.; George, A.; Ewing, L.; Tall, B. D.; Boyer, M. S.; Joseph, S. W.; Sapkota, A. R. Diversity, distribution and antibiotic resistance of Enterococcus spp. recovered from tomatoes, leaves, water and soil on U.S. Mid-Atlantic farms. Food Microbiol. 2013, 36, 465−474. (32) Taban, B. M.; Aytac, S. A.; Akkoc, N.; Akcelik, M. Characterization of antibiotic resistance in Salmonella enterica isolates determined from ready-to-eat (RTE) salad vegetables. Braz. J. Microbiol. 2013, 44, 385−391. (33) Yashiro, E.; McManus, P. S., Effect of streptomycin treatment on bacterial community structure in the apple phyllosphere. PLoS One 2012, 7, article e37131 10.1371/journal.pone.0037131 (34) Li, X.; Fernandez-Ortuno, D.; Grabke, A.; Schnabel, G. Resistance to fludioxonil in Botrytis cinerea isolates from blackberry and strawberry. Phytopathology 2014, 104, 724−732. (35) Petternel, C.; Galler, H.; Zarfel, G.; Luxner, J.; Haas, D.; Grisold, A. J.; Reinthaler, F. F.; Feierl, G. Isolation and characterization of multidrug-resistant bacteria from minced meat in Austria. Food Microbiol. 2014, 44, 41−46.

REFERENCES

(1) Chattopadhyay, M. K. Use of antibiotics as feed additives: a burning question. Front. Microbiol. 2014, 5, article 334 10.3389/ fmicb.2014.00334 (2) He, L. Y.; Liu, Y. S.; Su, H. C.; Zhao, J. L.; Liu, S. S.; Chen, J.; Liu, W. R.; Ying, G. G. Dissemination of antibiotic resistance genes in representative broiler feedlots environments: identification of indicator ARGs and correlations with environmental variables. Environ. Sci. Technol. 2014, 48, 13120−13129. (3) Udikovic-Kolic, N.; Wichmann, F.; Broderick, N. A.; Handelsman, J. Bloom of resident antibiotic-resistant bacteria in soil following manure fertilization. Proc. Natl. Acad. Sci. U.S.A. 2014, 111, 15202−15207. (4) Xue, K. Superbug, an epidemic begins. Harvard Mag. 2014 (May−June), 40−49. (5) Park, A. Man vs. microbe: we’re losing the battle against bacteria. Can we win the war? Time 2014 (May 19). (6) Blaser, M. J. Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues; Henry Holt: New York, 2014; p 288. (7) Yap, P. S.; Yiap, B. C.; Ping, H. C.; Lim, S. H. Essential oils, a new horizon in combating bacterial antibiotic resistance. Open Microbiol. J. 2014, 8, 6−14. (8) CDC. Antibiotics resistance threats in the United States. http:// www.cdc.gov/drugresistance/threat-report-2013/ (Jan 30, 2015). (9) Friedman, M.; Henika, P. R.; Mandrell, R. E. Bactericidal activities of plant essential oils and some of their isolated constituents against Campylobacter jejuni, Escherichia coli, Listeria monocytogenes, and Salmonella enterica. J. Food Prot. 2002, 65, 1545−1560 http:// www.ingentaconnect.com/content/iafp/jfp/2002/00000065/ 00000010/art00004. (10) Friedman, M.; Henika, P. R.; Levin, C. E.; Mandrell, R. E. Antibacterial activities of plant essential oils and their components against Escherichia coli O157:H7 and Salmonella enterica in apple juice. J. Agric. Food Chem. 2004, 52, 6042−6048. (11) Friedman, M. Chemistry and multi-beneficial bioactivities of carvacrol (4-isopropyl-2-methylphenol), a component of essential oils produced by aromatic plants and spices. J. Agric. Food Chem. 2014, 62, 7652−7670. (12) Friedman, M.; Buick, R.; Elliott, C. T. Antibacterial activities of naturally occurring compounds against antibiotic-resistant Bacillus cereus vegetative cells and spores, Escherichia coli, and Staphylococcus aureus. J. Food Prot. 2004, 67, 1774−1778 http://www.ingentaconnect. com/content/iafp/jfp/2004/00000067/00000008/art00034. (13) Friedman, M.; Henika, P. R.; Levin, C. E. Antimicrobial activities of red wine-based formulations containing plant extracts against Escherichia coli O157:H7 and Salmonella enterica serovar Hadar. Food Control 2015, 50, 652−658. (14) Wright, G. D. Something old, something new: revisiting natural products in antibiotic drug discovery. Can. J. Microbiol. 2014, 60, 147− 154. (15) Boonyasiri, A.; Tangkoskul, T.; Seenama, C.; Saiyarin, J.; Tiengrim, S.; Thamlikitkul, V. Prevalence of antibiotic resistant bacteria in healthy adults, foods, food animals, and the environment in selected areas in Thailand. Pathog. Global Health 2014, 108, 235− 245. (16) Frana, T. S.; Beahm, A. R.; Hanson, B. M.; Kinyon, J. M.; Layman, L. L.; Karriker, L. A.; Ramirez, A.; Smith, T. C. Isolation and characterization of methicillin-resistant Staphylococcus aureus from pork farms and visiting veterinary students. PLoS One 2013, 8, article e53738 10.1371/journal.pone.0053738 (17) Hiroi, M.; Kawamori, F.; Harada, T.; Sano, Y.; Miwa, N.; Sugiyama, K.; Hara-Kudo, Y.; Masuda, T. Antibiotic resistance in bacterial pathogens from retail raw meats and food-producing animals in Japan. J. Food Prot. 2012, 75, 1774−1782. (18) Alexander, T. W.; Inglis, G. D.; Yanke, L. J.; Topp, E.; Read, R. R.; Reuter, T.; McAllister, T. A. Farm-to-fork characterization of Escherichia coli associated with feedlot cattle with a known history of antimicrobial use. Int. J. Food Microbiol. 2010, 137, 40−48. L



Review

(36) Liu, Z.; Zhang, Z.; Yan, H.; Li, J.; Shi, L. Isolation and molecular characterization of multidrug-resistant Enterobacteriaceae strains from pork and environmental samples in Xiamen, China. J. Food Prot. 2015, 78, 78−88. (37) Lassok, B.; Tenhagen, B. A. From pig to pork: methicillinresistant Staphylococcus aureus in the pork production chain. J. Food Prot. 2013, 76, 1095−1108. (38) Abgottspon, H.; Stephan, R.; Bagutti, C.; Brodmann, P.; Hachler, H.; Zurfluh, K. Characteristics of extended-spectrum cephalosporin-resistant Escherichia coli isolated from Swiss and imported poultry meat. J. Food Prot. 2014, 77, 112−115. (39) Belmar Campos, C.; Fenner, I.; Wiese, N.; Lensing, C.; Christner, M.; Rohde, H.; Aepfelbacher, M.; Fenner, T.; Hentschke, M. Prevalence and genotypes of extended spectrum beta-lactamases in Enterobacteriaceae isolated from human stool and chicken meat in Hamburg, Germany. Int. J. Med. Microbiol. 2014, 304, 678−684. (40) Diarra, M. S.; Delaquis, P.; Rempel, H.; Bach, S.; Harlton, C.; Aslam, M.; Pritchard, J.; Topp, E. Antibiotic resistance and diversity of Salmonella enterica serovars associated with broiler chickens. J. Food Prot. 2014, 77, 40−49. (41) Dan, S. D.; Tabaran, A.; Mihaiu, L.; Mihaiu, M. Antibiotic susceptibility and prevalence of foodborne pathogens in poultry meat in Romania. J. Infect. Dev. Countries 2015, 9, 35−41. (42) Lavilla Lerma, L.; Benomar, N.; Casado Munoz Mdel, C.; Galvez, A.; Abriouel, H. Antibiotic multiresistance analysis of mesophilic and psychrotrophic Pseudomonas spp. isolated from goat and lamb slaughterhouse surfaces throughout the meat production process. Appl. Environ. Microbiol. 2014, 80, 6792−6806. (43) Gousia, P.; Economou, V.; Sakkas, H.; Leveidiotou, S.; Papadopoulou, C. Antimicrobial resistance of major foodborne pathogens from major meat products. Foodborne Pathog. Dis. 2011, 8, 27−38. (44) Yang, B.; Cui, Y.; Shi, C.; Wang, J.; Xia, X.; Xi, M.; Wang, X.; Meng, J.; Alali, W. Q.; Walls, I.; Doyle, M. P. Counts, serotypes, and antimicrobial resistance of Salmonella isolates on retail raw poultry in the People’s Republic of China. J. Food Prot. 2014, 77, 894−902. (45) Giacomelli, M.; Salata, C.; Martini, M.; Montesissa, C.; Piccirillo, A. Antimicrobial resistance of Campylobacter jejuni and Campylobacter coli from poultry in Italy. Microb. Drug Resist. 2014, 20, 181−188. (46) Raufu, I. A.; Fashae, K.; Ameh, J. A.; Ambali, A.; Ogunsola, F. T.; Coker, A. O.; Hendriksen, R. S. Persistence of fluoroquinoloneresistant Salmonella enterica serovar Kentucky from poultry and poultry sources in Nigeria. J. Infect. Dev. Countries 2014, 8, 384−388. (47) McNeece, G.; Naughton, V.; Woodward, M. J.; Dooley, J. S. G.; Naughton, P. J. Array based detection of antibiotic resistance genes in Gram negative bacteria isolated from retail poultry meat in the UK and Ireland. Int. J. Food Microbiol. 2014, 179, 24−32. (48) Ta, Y. T.; Nguyen, T. T.; To, P. B.; Pham da, X.; Le, H. T.; Thi, G. N.; Alali, W. Q.; Walls, I.; Doyle, M. P. Quantification, serovars, and antibiotic resistance of Salmonella isolated from retail raw chicken meat in Vietnam. J. Food Prot. 2014, 77, 57−66. (49) Sapkota, A. R.; Hulet, R. M.; Zhang, G.; McDermott, P.; Kinney, E. L.; Schwab, K. J.; Joseph, S. W. Lower prevalence of antibioticresistant enterococci on U.S. conventional poultry farms that transitioned to organic practices. Environ. Health Perspect. 2011, 119, 1622−1628. (50) Sapkota, A. R.; Kinney, E. L.; George, A.; Hulet, R. M.; CruzCano, R.; Schwab, K. J.; Zhang, G.; Joseph, S. W. Lower prevalence of antibiotic-resistant Salmonella on large-scale U.S. conventional poultry farms that transitioned to organic practices. Sci. Total Environ. 2014, 476−477, 387−392. (51) Smith-Spangler, C.; Brandeau, M. L.; Hunter, G. E.; Clay Bavinger, J.; Pearson, M.; Eschbach, P. J.; Sundaram, V.; Liu, H.; Schirmer, P.; Stave, C.; Olkin, I.; Bravata, D. M. Are organic foods safer or healthier than conventional alternatives? A systematic review. Ann. Intern. Med. 2012, 157, 348−366. (52) Mollenkopf, D. F.; Cenera, J. K.; Bryant, E. M.; King, C. A.; Kashoma, I.; Kumar, A.; Funk, J. A.; Rajashekara, G.; Wittum, T. E.

Organic or antibiotic-free labeling does not impact the recovery of enteric pathogens and antimicrobial-resistant Escherichia coli from fresh retail chicken. Foodborne Pathog. Dis. 2014, 11, 920−929. (53) Adzitey, F.; Huda, N.; Rahmat Ali, G. R. Prevalence and antibiotic resistance of Campylobacter, Salmonella, and L. monocytogenes in ducks: a review. Foodborne Pathog. Dis. 2012, 9, 498−505. (54) Rasheed, M. U.; Thajuddin, N.; Ahamed, P.; Teklemariam, Z.; Jamil, K. Antimicrobial drug resistance in strains of Escherichia coli isolated from food sources. Rev. Inst. Med. Trop. Sao Paulo 2014, 56, 341−346. (55) Sultana, F.; Kamrunnahar; Afroz, H.; Jahan, A.; Fakruddin, M.; Datta, S. Multi-antibiotic resistant bacteria in frozen food (ready to cook food) of animal origin sold in Dhaka, Bangladesh. Asian Pac. J. Trop. Biomed. 2014, 4, S268−S271. (56) Chajȩcka-Wierzchowska, W.; Zadernowska, A.; Nalepa, B.; Sierpińska, M.; Łaniewska-Trokenheim, Ł. Retail ready-to-eat food as a potential vehicle for Staphylococcus spp. harboring antibiotic resistance genes. J. Food Prot. 2014, 77, 993−998. (57) Elhadi, N. Prevalence and antimicrobial resistance of Salmonella spp. In raw retail frozen imported freshwater fish to Eastern Province of Saudi Arabia. Asian Pac. J. Trop. Biomed. 2014, 4, 234−238. (58) Moore, J. E.; Huang, J.; Yu, P.; Ma, C.; Moore, P. J. A.; Millar, B. C.; Goldsmith, C. E.; Xu, J. High diversity of bacterial pathogens and antibiotic resistance in salmonid fish farm pond water as determined by molecular identification employing 16S rDNA PCR, gene sequencing and total antibiotic susceptibility techniques. Ecotoxicol. Environ. Saf. 2014, 108, 281−286. (59) Kang, C. H.; Shin, Y.; Jeon, H.; Choi, J. H.; Jeong, S.; So, J. S. Antibiotic resistance of Shewanella putrefaciens isolated from shellfish collected from the West Sea in Korea. Mar. Pollut. Bull. 2013, 76, 85− 88. (60) Yu, L.; Zhou, Y.; Wang, R.; Lou, J.; Zhang, L.; Li, J.; Bi, Z.; Kan, B. Multiple antibiotic resistance of Vibrio cholerae serogroup O139 in China from 1993 to 2009. PLoS One 2012, 7, article e38633 10.1371/ journal.pone.0038633. (61) Duran, G. M.; Marshall, D. L. Ready-to-eat shrimp as an international vehicle of antibiotic-resistant bacteria. J. Food Prot. 2005, 68, 2395−2401 http://www.ingentaconnect.com/content/iafp/jfp/ 2005/00000068/00000011/art00020. (62) Ahmed, A. M.; Shimamoto, T.; Shimamoto, T. Characterization of integrons and resistance genes in multidrug-resistant Salmonella enterica isolated from meat and dairy products in Egypt. Int. J. Food Microbiol. 2014, 189, 39−44. (63) Pesavento, G.; Calonico, C.; Ducci, B.; Magnanini, A.; Lo Nostro, A. Prevalence and antibiotic resistance of Enterococcus spp. isolated from retail cheese, ready-to-eat salads, ham, and raw meat. Food Microbiol. 2014, 41, 1−7. (64) Silveira-Filho, V. M.; Luz, I. S.; Campos, A. P.; Silva, W. M.; Barros, M. P.; Medeiros, E. S.; Freitas, M. F.; Mota, R. A.; Sena, M. J.; Leal-Balbino, T. C. Antibiotic resistance and molecular analysis of Staphylococcus aureus isolated from cow’s milk and dairy products in northeast Brazil. J. Food Prot. 2014, 77, 583−591. (65) Osman, K. M.; Zolnikov, T. R.; Samir, A.; Orabi, A. Prevalence, pathogenic capability, virulence genes, biofilm formation, and antibiotic resistance of Listeria in goat and sheep milk confirms need of hygienic milking conditions. Pathog. Global Health 2014, 108, 21− 29. (66) D’Amico, D. J.; Druart, M. J.; Donnelly, C. W. Comparing the behavior of multidrug-resistant and pansusceptible Salmonella during the production and aging of a Gouda cheese manufactured from raw milk. J. Food Prot. 2014, 77, 903−913. (67) Musgrove, M. T.; Jones, D. R.; Northcutt, J. K.; Cox, N. A.; Harrison, M. A.; Fedorka-Cray, P. J.; Ladely, S. R. Antimicrobial resistance in Salmonella and Escherichia coli isolated from commercial shell eggs. Poult. Sci. 2006, 85, 1665−1669. (68) Duffy, G.; Walsh, C.; Blair, I. S.; McDowell, D. A. Survival of antibiotic resistant and antibiotic sensitive strains of E. coli O157 and E. coli O26 in food matrices. Int. J. Food Microbiol. 2006, 109, 179− 186. M



Review

active against methicillin-resistant Staphylococcus aureus. Appl. Microbiol. Biotechnol. 2015, 99, 741−752. (90) Friedman, M.; Buick, R.; Elliott, C. T. Antimicrobial activities of plant compounds against antibiotic-resistant Micrococcus luteus. Int. J. Antimicrob. Agents 2006, 28, 156−158. (91) Johny, A. K.; Hoagland, T.; Venkitanarayanan, K. Effect of subinhibitory concentrations of plant-derived molecules in increasing the sensitivity of multidrug-resistant Salmonella enterica serovar Typhimurium DT104 to antibiotics. Foodborne Pathog. Dis. 2010, 7, 1165−1170. (92) Gibbons, S.; Oluwatuyi, M.; Veitch, N. C.; Gray, A. I. Bacterial resistance modifying agents from Lycopus europaeus. Phytochemistry 2003, 62, 83−87. (93) Oluwatuyi, M.; Kaatz, G. W.; Gibbons, S. Antibacterial and resistance modifying activity of Rosmarinus of f icinalis. Phytochemistry 2004, 65, 3249−3254. (94) Chan, B. C.; Ip, M.; Lau, C. B.; Lui, S. L.; Jolivalt, C.; GanemElbaz, C.; Litaudon, M.; Reiner, N. E.; Gong, H.; See, R. H.; Fung, K. P.; Leung, P. C. Synergistic effects of baicalein with ciprofloxacin against NorA over-expressed methicillin-resistant Staphylococcus aureus (MRSA) and inhibition of MRSA pyruvate kinase. J. Ethnopharmacol. 2011, 137, 767−773. (95) Peng, Q.; Zhou, S.; Yao, F.; Hou, B.; Huang, Y.; Hua, D.; Zheng, Y.; Qian, Y. Baicalein suppresses the SOS response system of Staphylococcus aureus induced by ciprofloxacin. Cell. Physiol. Biochem. 2011, 28, 1045−1050. (96) Karunanidhi, A.; Thomas, R.; van Belkum, A.; Neela, V. In vitro antibacterial and antibiofilm activities of chlorogenic acid against clinical isolates of Stenotrophomonas maltophilia including the trimethoprim/sulfamethoxazole resistant strain. BioMed Res. Int. 2013, 2013, article 392058 10.1155/2013/584549 (97) Alves, M. J.; Ferreira, I. C.; Froufe, H. J.; Abreu, R. M.; Martins, A.; Pintado, M. Antimicrobial activity of phenolic compounds identified in wild mushrooms, SAR analysis and docking studies. J. Appl. Microbiol. 2013, 115, 346−357. (98) Alves, M. J.; Ferreira, I. C.; Dias, J.; Teixeira, V.; Martins, A.; Pintado, M. A review on antimicrobial activity of mushroom (Basidiomycetes) extracts and isolated compounds. Planta Med. 2012, 78, 1707−1718. (99) Friedman, M.; Henika, P. R.; Mandrell, R. E. Antibacterial activities of phenolic benzaldehydes and benzoic acids against Campylobacter jejuni, Escherichia coli, Listeria monocytogenes, and Salmonella enterica. J. Food Prot. 2003, 66, 1811−1821 http://www. ingentaconnect.com/content/iafp/jfp/2003/00000066/00000010/ art00011. (100) Klančnik, A.; Možina, S. S.; Zhang, Q. Anti-Campylobacter activities and resistance mechanisms of natural phenolic compounds in Campylobacter. PLoS One 2012, 7, article e51800 10.1371/journal.pone.0051800 (101) Gallucci, M. N.; Carezzano, M. E.; Oliva, M. M.; Demo, M. S.; Pizzolitto, R. P.; Zunino, M. P.; Zygadlo, J. A.; Dambolena, J. S. In vitro activity of natural phenolic compounds against fluconazoleresistant Candida species: a quantitative structure-activity relationship analysis. J. Appl. Microbiol. 2014, 116, 795−804. (102) Chen, Y. L.; Huang, S. T.; Sun, F. M.; Chiang, Y. L.; Chiang, C. J.; Tsai, C. M.; Weng, C. J. Transformation of cinnamic acid from trans- to cis-form raises a notable bactericidal and synergistic activity against multiple-drug resistant Mycobacterium tuberculosis. Eur. J. Pharm. Sci. 2011, 43, 188−194. (103) Lipińska L, K. E. S. M. The structure, occurrence and biological activity of ellagitannins: a general review. Acta Sci. Pol., Technol. Aliment. 2014, 13, 289−299. (104) Kim, S. K.; Kim, H.; Kim, S. A.; Park, H. K.; Kim, W. Antiinflammatory and anti-superbacterial activity of polyphenols isolated from black raspberry. Korean J. Physiol. Pharmacol. 2013, 17, 73−79. (105) Bag, A.; Chattopadhyay, R. R. Efflux-pump inhibitory activity of a gallotannin from Terminalia chebula fruit against multidrugresistant uropathogenic Escherichia coli. Nat. Prod. Res. 2014, 28, 1280−1283.

(69) Frickmann, H.; Masanta, W. O.; Zautner, A. E. Emerging rapid resistance testing methods for clinical microbiology laboratories and their potential impact on patient management. BioMed Res. Int. 2014, 2014, article 375681 10.1155/2014/375681 (70) Zboromyrska, Y.; Ferrer-Navarro, M.; Marco, F.; Vila, J. [Detection of antibacterial resistance by MALDI-TOF mass spectrometry]. Rev. Esp. Quimioter. 2014, 27, 87−92 http://seq.es/ seq/0214-3429/27/2/yuliya.pdf. (71) Iqbal, J.; Siddiqui, R.; Kazmi, S. U.; Khan, N. A. A simple assay to screen antimicrobial compounds potentiating the activity of current antibiotics. BioMed. Res. Int. 2013, 2013, article 927323 10.1155/2013/ 927323 (72) Allen, H. K.; Trachsel, J.; Looft, T.; Casey, T. A. Finding alternatives to antibiotics. Ann. N. Y. Acad. Sci. 2014, 1323, 91−100. (73) Patra, A. K.; Saxena, J. The effect and mode of action of saponins on the microbial populations and fermentation in the rumen and ruminant production. Nutr. Res. Rev. 2009, 22, 204−219. (74) Brown, D. G.; Lister, T.; May-Dracka, T. L. New natural products as new leads for antibacterial drug discovery. Bioorg. Med. Chem. Lett. 2014, 24, 413−418. (75) Callaway, T. R.; Anderson, R. C.; Edrington, T. S.; Genovese, K. J.; Harvey, R. B.; Poole, T. L.; Nisbet, D. J. Recent pre-harvest supplementation strategies to reduce carriage and shedding of zoonotic enteric bacterial pathogens in food animals. Anim. Health Res. Rev. 2004, 5, 35−47. (76) White, D. G.; Zhao, S.; Singh, R.; McDermott, P. F. Antimicrobial resistance among Gram-negative foodborne bacterial pathogens associated with foods of animal origin. Foodborne Pathog. Dis. 2004, 1, 137−152. (77) Clardy, J.; Fischbach, M. A.; Walsh, C. T. New antibiotics from bacterial natural products. Nat. Biotechnol. 2006, 24, 1541−1550. (78) Wang, J.; Kodali, S.; Lee, S. H.; Galgoci, A.; Painter, R.; Dorso, K.; Racine, F.; Motyl, M.; Hernandez, L.; Tinney, E.; Colletti, S. L.; Herath, K.; Cummings, R.; Salazar, O.; Gonzalez, I.; Basilio, A.; Vicente, F.; Genilloud, O.; Pelaez, F.; Jayasuriya, H.; Young, K.; Cully, D. F.; Singh, S. B. Discovery of platencin, a dual FabF and FabH inhibitor with in vivo antibiotic properties. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 7612−7616. (79) Walsh, C.; Fanning, S. Antimicrobial resistance in foodborne pathogens–a cause for concern? Curr. Drug Targets 2008, 9, 808−815. (80) Fischbach, M. A.; Walsh, C. T. Antibiotics for emerging pathogens. Science 2009, 325, 1089−1093. (81) Doyle, M. P.; Erickson, M. C. Opportunities for mitigating pathogen contamination during on-farm food production. Int. J. Food Microbiol. 2012, 152, 54−74. (82) Doyle, M. E.; Hartmann, F. A.; Lee Wong, A. C. Methicillinresistant staphylococci: implications for our food supply? Anim. Health Res. Rev. 2012, 13, 157−180. (83) Hur, J.; Jawale, C.; Lee, J. H. Antimicrobial resistance of Salmonella isolated from food animals: a review. Food Res. Int. 2012, 45, 819−830. (84) Oliveira, H.; Azeredo, J.; Lavigne, R.; Kluskens, L. D. Bacteriophage endolysins as a response to emerging foodborne pathogens. Trends Food Sci. Technol. 2012, 28, 103−115. (85) Capita, R.; Alonso-Calleja, C. Antibiotic-resistant bacteria: a challenge for the food industry. Crit. Rev. Food Sci. Nutr. 2013, 53, 11− 48. (86) Rutkowski, J.; Brzezinski, B. Structures and properties of naturally occurring polyether antibiotics. BioMed. Res. Int. 2013, 2013, article 16251310.1155/2014/162513. (87) Gyawali, R.; Ibrahim, S. A. Natural products as antimicrobial agents. Food Control 2014, 46, 412−429. (88) Jassim, S. A. A.; Limoges, R. G. Natural solution to antibiotic resistance: bacteriophages ‘The Living Drugs’. World J. Microbiol. Biotechnol. 2014, 30, 2153−2170. (89) Linden, S. B.; Zhang, H.; Heselpoth, R. D.; Shen, Y.; Schmelcher, M.; Eichenseher, F.; Nelson, D. C. Biochemical and biophysical characterization of PlyGRCS, a bacteriophage endolysin N



Review

resistant staphylococci to oregano essential oil, carvacrol and thymol. FEMS Microbiol. Lett. 2004, 230, 191−195. (123) Shin, S.; Kim, J. H. In vitro inhibitory activities of essential oils from two Korean Thymus species against antibiotic-resistant pathogens. Arch. Arch. Pharmacal Res. 2005, 28, 897−901. (124) Palaniappan, K.; Holley, R. A. Use of natural antimicrobials to increase antibiotic susceptibility of drug resistant bacteria. Int. J. Food Microbiol. 2010, 140, 164−168. (125) Ravishankar, S.; Zhu, L.; Law, B.; Joens, L.; Friedman, M. Plant-derived compounds inactivate antibiotic-resistant Campylobacter jejuni strains. J. Food Prot. 2008, 71, 1145−1149 http://www. ingentaconnect.com/content/iafp/jfp/2008/00000071/00000006/ art00006. (126) Mild, R. M.; Joens, L. A.; Friedman, M.; Olsen, C. W.; McHugh, T. H.; Law, B.; Ravishankar, S. Antimicrobial edible apple films inactivate antibiotic resistant and susceptible Campylobacter jejuni strains on chicken breast. J. Food Sci. 2011, 76, M163−M168. (127) Ravishankar, S.; Zhu, L.; Reyna-Granados, J.; Law, B.; Joens, L.; Friedman, M. Carvacrol and cinnamaldehyde inactivate antibioticresistant Salmonella enterica in buffer and on celery and oysters. J. Food Prot. 2010, 73, 234−240 http://www.ingentaconnect.com/content/ iafp/jfp/2003/00000066/00000010/art00011. (128) Upadhyaya, I.; Upadhyay, A.; Kollanoor-Johny, A.; Baskaran, S. A.; Mooyottu, S.; Darre, M. J.; Venkitanarayanan, K. Rapid inactivation of Salmonella Enteritidis on shell eggs by plant-derived antimicrobials. Poult. Sci. 2013, 92, 3228−3235. (129) Friedman, M. Antibiotic activities of plant compounds against non-resistant and antibiotic-resistant foodborne human pathogens. ACS Symp. Ser. 2006, No. 931, 167−183. (130) Halcón, L.; Milkus, K. Staphylococcus aureus and wounds: a review of tea tree oil as a promising antimicrobial. Am. J. Infect. Control 2004, 32, 402−408. (131) Thomsen, N. A.; Hammer, K. A.; Riley, T. V.; Van Belkum, A.; Carson, C. F. Effect of habituation to tea tree (Melaleuca alternifolia) oil on the subsequent susceptibility of Staphylococcus spp. to antimicrobials, triclosan, tea tree oil, terpinen-4-ol and carvacrol. Int. J. Antimicrob. Agents 2013, 41, 343−351. (132) Fadli, M.; Chevalier, J.; Hassani, L.; Mezrioui, N. E.; Pages, J. M. Natural extracts stimulate membrane-associated mechanisms of resistance in Gram-negative bacteria. Lett. Appl. Microbiol. 2014, 58, 472−477. (133) Fadli, M.; Chevalier, J.; Bolla, J. M.; Mezrioui, N. E.; Hassani, L.; Pages, J. M. Thymus maroccanus essential oil, a membranotropic compound active on Gram-negative bacteria and resistant isolates. J. Appl. Microbiol. 2012, 113, 1120−1129. (134) Medeiros Barreto, H.; Cerqueira Fontinele, F.; Pereira de Oliveira, A.; Arcanjo, D. D.; Cavalcanti Dos Santos, B. H.; de Abreu, A. P.; Douglas Melo Coutinho, H.; Alves Carvalho da Silva, R.; Oliveira de Sousa, T.; Freire de Medeiros, M.; Lopes Cito, A. M.; Dantas Lopes, J. A. Phytochemical prospection and modulation of antibiotic activity in vitro by Lippia origanoides H.B.K. in methicillin resistant Staphylococcus aureus. BioMed Res. Int. 2014, 2014, article 305610.10.1155/2014/305610 (135) Choi, J. G.; Kang, O. H.; Lee, Y. S.; Oh, Y. C.; Chae, H. S.; Jang, H. J.; Shin, D. W.; Kwon, D. Y. Antibacterial activity of methyl gallate isolated from Galla Rhois or carvacrol combined with nalidixic acid against nalidixic acid resistant bacteria. Molecules 2009, 14, 1773− 1780. (136) Langeveld, W. T.; Veldhuizen, E. J.; Burt, S. A. Synergy between essential oil components and antibiotics: a review. Crit. Rev. Microbiol. 2014, 40, 76−94. (137) Yap, P. S.; Lim, S. H.; Hu, C. P.; Yiap, B. C. Combination of essential oils and antibiotics reduce antibiotic resistance in plasmidconferred multidrug resistant bacteria. Phytomedicine 2013, 20, 710− 713. (138) Ahmad, A.; Khan, A.; Manzoor, N. Reversal of efflux mediated antifungal resistance underlies synergistic activity of two monoterpenes with fluconazole. Eur. J. Pharm. Sci. 2013, 48, 80−86.

(106) Caballero Gomez, N.; Abriouel, H.; Grande, M. J.; Perez Pulido, R.; Galvez, A. Combined treatments of enterocin AS-48 with biocides to improve the inactivation of methicillin-sensitive and methicillin-resistant Staphylococcus aureus planktonic and sessile cells. Int. J. Food Microbiol. 2013, 163, 96−100. (107) Balciunas, E. M.; Castillo Martinez, F. A.; Todorov, S. D.; Franco, B. D. G. D. M.; Converti, A.; Oliveira, R. P. D. S. Novel biotechnological applications of bacteriocins: a review. Food Control 2013, 32, 134−142. (108) Marks, L. R.; Clementi, E. A.; Hakansson, A. P. The human milk protein-lipid complex HAMLET sensitizes bacterial pathogens to traditional antimicrobial agents. PLoS One 2012, 7, article e43514.10.1371/journal.pone.0043514 (109) Chung, P. Y.; Chung, L. Y.; Navaratnam, P. Potential targets by pentacyclic triterpenoids from Callicarpa farinosa against methicillinresistant and sensitive Staphylococcus aureus. Fitoterapia 2014, 94, 48− 54. (110) Friedman, M. Anticarcinogenic, cardioprotective, and other health benefits of tomato compounds lycopene, α-tomatine, and tomatidine in pure form and in fresh and processed tomatoes. J. Agric. Food Chem. 2013, 61, 9534−9550. (111) Mitchell, G.; Lafrance, M.; Boulanger, S.; Séguin, D. L.; Guay, I.; Gattuso, M.; Marsault, E.; Bouarab, K.; Malouin, F. Tomatidine acts in synergy with aminoglycoside antibiotics against multiresistant Staphylococcus aureus and prevents virulence gene expression. J. Antimicrob. Chemother. 2012, 67, 559−568. (112) Friedman, M. Potato glycoalkaloids and metabolites: roles in the plant and in the diet. J. Agric. Food Chem. 2006, 54, 8655−8681. (113) Friedman, M.; Henika, P. R.; Levin, C. E.; Mandrell, R. E. Antimicrobial wine formulations active against the foodborne pathogens Escherichia coli O157:H7 and Salmonella enterica. J. Food Sci. 2006, 71, M245−M251. (114) Rojas-Graü, M. A.; Avena-Bustillos, R. J.; Friedman, M.; Henika, P. R.; Martin-Belloso, O.; McHugh, T. H. Mechanical, barrier, and antimicrobial properties of apple puree edible films containing plant essential oils. J. Agric. Food Chem. 2006, 54, 9262−9267. (115) Wong, S. Y. Y.; Grant, I. R.; Friedman, M.; Elliott, C. T.; Situ, C. Antibacterial activities of naturally occurring compounds against Mycobacterium avium subsp. paratuberculosis. Appl. Environ. Microbiol. 2008, 74, 5986−5990. (116) Du, W. X.; Olsen, C. W.; Avena-Bustillos, R. J.; McHugh, T. H.; Levin, C. E.; Friedman, M. Effects of allspice, cinnamon, and clove bud essential oils in edible apple films on physical properties and antimicrobial activities. J. Food Sci. 2009, 74, M372−M378. (117) Du, W.-X.; Olsen, C. W.; Avena-Bustillos, R. J.; McHugh, T. H.; Levin, C. E.; Mandrell, R.; Friedman, M. Antibacterial effects of allspice, garlic, and oregano essential oils in tomato films determined by overlay and vapor-phase methods. J. Food Sci. 2009, 74, M390− M397. (118) Moore-Neibel, K.; Gerber, C.; Patel, J.; Friedman, M.; Ravishankar, S. Antimicrobial activity of lemongrass oil against Salmonella enterica on organic leafy greens. J. Appl. Microbiol. 2012, 112, 485−492. (119) Rounds, L.; Havens, C. M.; Feinstein, Y.; Friedman, M.; Ravishankar, S. Plant extracts, spices, and essential oils inactivate Escherichia coli O157:H7 and reduce formation of potentially carcinogenic heterocyclic amines in cooked beef patties. J. Agric. Food Chem. 2012, 60, 3792−3799. (120) Chen, C. H.; Ravishankar, S.; Marchello, J.; Friedman, M. Antimicrobial activity of plant compounds against Salmonella Typhimurium DT104 in ground pork and the influence of heat and storage on the antimicrobial activity. J. Food Prot. 2013, 76, 1264− 1269. (121) Todd, J.; Friedman, M.; Patel, J.; Jaroni, D.; Ravishankar, S. The antimicrobial effects of cinnamon leaf oil against multi-drug resistant Salmonella Newport on organic leafy greens. Int. J. Food Microbiol. 2013, 166, 193−199. (122) Nostro, A.; Blanco, A. R.; Cannatelli, M. A.; Enea, V.; Flamini, G.; Morelli, I.; Roccaro, A. S.; Alonzo, V. Susceptibility of methicillinO



Review

(139) Verlinden, M.; Pasmans, F.; Mahu, M.; Vande Maele, L.; De Pauw, N.; Yang, Z.; Haesebrouck, F.; Martel, A. In vitro sensitivity of poultry Brachyspira intermedia isolates to essential oil components and in vivo reduction of Brachyspira intermedia in rearing pullets with cinnamaldehyde feed supplementation. Poult. Sci. 2013, 92, 1202− 1207. (140) Hannan, A.; Ikram Ullah, M.; Usman, M.; Hussain, S.; Absar, M.; Javed, K. Anti-mycobacterial activity of garlic (Allium sativum) against multi-drug resistant and non-multi-drug resistant mycobacterium tuberculosis. Pak. J. Pharm. Sci. 2011, 24, 81−85 http://www. pjps.pk/wp-content/uploads/pdfs/CD-PJPS-24-1-11/Paper-15.pdf. (141) Fani, M. M.; Kohanteb, J.; Dayaghi, M. Inhibitory activity of garlic (Allium sativum) extract on multidrug-resistant Streptococcus mutans. J. Indian Soc. Pedod. Prev. Dent. 2007, 25, 164−168. (142) Tirado, D. J.; Hudson, N. R.; Maldonado, C. J. Efficacy of medical grade honey against multidrug-resistant organisms of operational significance: part I. J. Trauma Acute Care Surg. 2014, 77, S204−S207. (143) Müller, P.; Alber, D. G.; Turnbull, L.; Schlothauer, R. C.; Carter, D. A.; Whitchurch, C. B.; Harry, E. J. Synergism between Medihoney and rifampicin against methicillin-resistant Staphylococcus aureus (MRSA). PLoS One 2013, 8, article e57679, 10.1371/ journal.pone.0057679. (144) Al-Waili, N.; Al-Ghamdi, A.; Ansari, M. J.; Al-Attal, Y.; Salom, K. Synergistic effects of honey and propolis toward drug multiresistant Staphylococcus aureus, Escherichia coli and Candida albicans isolates in single and polymicrobial cultures. Int. J. Med. Sci. 2012, 9, 793−800. (145) Kwakman, P. H.; Zaat, S. A. Antibacterial components of honey. IUBMB Life 2012, 64, 48−55. (146) Ramesh, V.; Arivudainambi, U.; Thalavaipandian, A.; Karunakaran, C.; Rajendran, A. Antibacterial activity of wild Xylaria sp. strain R005 (Ascomycetes) against multidrug-resistant Staphylococcus aureus and Pseudomonas aeruginosa. Int. J. Med. Mushrooms 2012, 14, 47−53. (147) Noumedem, J. A.; Mihasan, M.; Kuiate, J. R.; Stefan, M.; Cojocaru, D.; Dzoyem, J. P.; Kuete, V. In vitro antibacterial and antibiotic-potentiation activities of four edible plants against multidrug-resistant gram-negative species. BMC Complement. Altern. Med. 2013, 13, 190. (148) Khameneh, B.; Iranshahy, M.; Ghandadi, M.; Ghoochi Atashbeyk, D.; Fazly Bazzaz, B. S.; Iranshahi, M. Investigation of the antibacterial activity and efflux pump inhibitory effect of co-loaded piperine and gentamicin nanoliposomes in methicillin-resistant Staphylococcus aureus. Drug Dev. Ind. Pharm. 2014, DOI: 10.3109/ 03639045.2014.920025. (149) Dey, D.; Debnath, S.; Hazra, S.; Ghosh, S.; Ray, R.; Hazra, B. Pomegranate pericarp extract enhances the antibacterial activity of ciprofloxacin against extended-spectrum beta-lactamase (ESBL) and metallo-beta-lactamase (MBL) producing Gram-negative bacilli. Food Chem. Toxicol. 2012, 50, 4302−4309. (150) Hafidh, R. R.; Abdulamir, A. S.; Vern, L. S.; Abu Bakar, F.; Abas, F.; Jahanshiri, F.; Sekawi, Z. Inhibition of growth of highly resistant bacterial and fungal pathogens by a natural product. Open Microbiol. J. 2011, 5, 96−106. (151) Friedman, M.; Henika, P. R.; Levin, C. E.; Mandrell, R. E.; Kozukue, N. Antimicrobial activities of tea catechins and theaflavins and tea extracts against Bacillus cereus. J. Food Prot. 2006, 69, 354−361 http://www.ingentaconnect.com/content/iafp/jfp/2006/00000069/ 00000002/art00015. (152) Friedman, M. Overview of antibacterial, antitoxin, antiviral, and antifungal activities of tea flavonoids and teas. Mol. Nutr. Food Res. 2007, 51, 116−134. (153) Stapleton, P. D.; Shah, S.; Anderson, J. C.; Hara, Y.; HamiltonMiller, J. M.; Taylor, P. W. Modulation of β-lactam resistance in Staphylococcus aureus by catechins and gallates. Int. J. Antimicrob. Agents 2004, 23, 462−467.

(154) Friedman, M.; Levin, C. E.; Lee, S.-U.; Kozukue, N. Stability of green tea catechins in commercial tea leaves during storage for 6 months. J. Food Sci. 2009, 74, H47−H51. (155) Heck, C. I.; de Mejia, E. G. Yerba mate tea (Ilex paraguariensis): a comprehensive review on chemistry, health implications, and technological considerations. J. Food Sci. 2007, 72, R138−R151. (156) Burris, K. P.; Higginbotham, K. L.; Stewart, C. Aqueous extracts of yerba mate as bactericidal agents against methicillinresistant Staphylococcus aureus in a microbiological medium and ground beef mixtures. Food Control 2015, 50, 748−753. (157) Jun, J. W.; Kim, H. J.; Yun, S. K.; Chai, J. Y.; Park, S. C. Eating oysters without risk of vibriosis: application of a bacteriophage against Vibrio parahaemolyticus in oysters. Int. J. Food Microbiol. 2014, 188, 31−35. (158) Qiang, Z.; Macauley, J. J.; Mormile, M. R.; Surampalli, R.; Adams, C. D. Treatment of antibiotics and antibiotic resistant bacteria in swine wastewater with free chlorine. J. Agric. Food Chem. 2006, 54, 8144−8154. (159) Oscar, T. P.; Tasmin, R.; Parveen, S. Chlorine inactivation of nonresistant and antibiotic-resistant strains of Salmonella Typhimurium isolated from chicken carcasses. J. Food Prot. 2013, 76, 1031− 1034. (160) Stopforth, J. D.; Suhalim, R.; Kottapalli, B.; Hill, W. E.; Samadpour, M. Thermal inactivation D- and z-values of multidrugresistant and non-multidrug-resistant Salmonella serotypes and survival in ground beef exposed to consumer-style cooking. J. Food Prot. 2008, 71, 509−515 http://www.ingentaconnect.com/content/iafp/jfp/ 2008/00000071/00000003/art00007. (161) Shen, C.; Geornaras, I.; Belk, K. E.; Smith, G. C.; Sofos, J. N. Inactivation of Escherichia coli O157:H7 in moisture-enhanced nonintact beef by pan-broiling or roasting with various cooking appliances set at different temperatures. J. Food Sci. 2011, 76, M64− M71. (162) Sagarzazu, N.; Cebrian, G.; Pagan, R.; Condon, S.; Manas, P. Emergence of pulsed electric fields resistance in Salmonella enterica serovar Typhimurium SL1344. Int. J. Food Microbiol. 2013, 166, 219− 225. (163) Huang, J. J.; Tang, F.; Xi, J. Y.; Pang, Y. C.; Hu, H. Y. [Inactivation and reactivation of antibiotic-resistant bacteria during and after UV disinfection in reclaimed water]. Huanjing Kexue 2014, 35, 1326−1331. (164) Rizzo, L.; Della Sala, A.; Fiorentino, A.; Li Puma, G. Disinfection of urban wastewater by solar driven and UV lamp TiO2 photocatalysis: effect on a multi drug resistant Escherichia coli strain. Water Res. 2014, 53, 145−152. (165) McKinney, J. M.; Williams, R. C.; Boardman, G. D.; Eifert, J. D.; Sumner, S. S. Effect of acid stress, antibiotic resistance, and heat shock on the resistance of Listeria monocytogenes to UV light when suspended in distilled water and fresh brine. J. Food Prot. 2009, 72, 1634−1640 http://www.ingentaconnect.com/content/iafp/jfp/2009/ 00000072/00000008/art00006. (166) Neetoo, H.; Nekoozadeh, S.; Jiang, Z.; Chen, H. Application of high hydrostatic pressure to decontaminate green onions from Salmonella and Escherichia coli O157:H7. Food Microbiol. 2011, 28, 1275−1283. (167) Reddy, N. R.; Marshall, K. M.; Morrissey, T. R.; Loeza, V.; Patazca, E.; Skinner, G. E.; Krishnamurthy, K.; Larkin, J. W. Combined high pressure and thermal processing on inactivation of type A and proteolytic type B spores of Clostridium botulinum. J. Food Prot. 2013, 76, 1384−1392. (168) Sun, J.; Deng, Z.; Yan, A. Bacterial multidrug efflux pumps: mechanisms, physiology and pharmacological exploitations. Biochem. Biophys. Res. Commun. 2014, 453, 254−267. (169) Blair, J. M.; Richmond, G. E.; Piddock, L. J. Multidrug efflux pumps in Gram-negative bacteria and their role in antibiotic resistance. Future Microbiol. 2014, 9, 1165−1177. P



Review

(170) Blair, J. M.; Webber, M. A.; Baylay, A. J.; Ogbolu, D. O.; Piddock, L. J. Molecular mechanisms of antibiotic resistance. Nat. Rev. Microbiol. 2015, 13, 42−51. (171) Klančnik, A.; Gröblacher, B.; Kovač, J.; Bucar, F.; Možina, S. S. Anti-Campylobacter and resistance-modifying activity of Alpinia katsumadai seed extracts. J. Appl. Microbiol. 2012, 113, 1249−1262. (172) Ohene-Agyei, T.; Mowla, R.; Rahman, T.; Venter, H. Phytochemicals increase the antibacterial activity of antibiotics by acting on a drug efflux pump. Microbiol. Open 2014, 3, 885−896. (173) Du, D.; Wang, Z.; James, N. R.; Voss, J. E.; Klimont, E.; Ohene-Agyei, T.; Venter, H.; Chiu, W.; Luisi, B. F. Structure of the AcrAB-TolC multidrug efflux pump. Nature 2014, 509, 512−515. (174) Sung, W. S.; Lee, D. G. Mechanism of decreased susceptibility for Gram-negative bacteria and synergistic effect with ampicillin of indole-3-carbinol. Biol. Pharm. Bull. 2008, 31, 1798−1801. (175) Ojeda-Sana, A. M.; Repetto, V.; Moreno, S. Carnosic acid is an efflux pumps modulator by dissipation of the membrane potential in Enterococcus faecalis and Staphylococcus aureus. World J. Microbiol. Biotechnol. 2013, 29, 137−144. (176) Fadli, M.; Bolla, J. M.; Mezrioui, N. E.; Pagès, J. M.; Hassani, L. First evidence of antibacterial and synergistic effects of Thymus riatarum essential oil with conventional antibiotics. Ind. Crops Prod. 2014, 61, 370−376. (177) Jakobsen, T. H.; Bragason, S. K.; Phipps, R. K.; Christensen, L. D.; van Gennip, M.; Alhede, M.; Skindersoe, M.; Larsen, T. O.; Høiby, N.; Bjarnsholt, T.; Givskov, M. Food as a source for quorum sensing inhibitors: iberin from horseradish revealed as a quorum sensing inhibitor of Pseudomonas aeruginosa. Appl. Environ. Microbiol. 2012, 78, 2410−2421. (178) Chang, C. Y.; Krishnan, T.; Wang, H.; Chen, Y.; Yin, W. F.; Chong, Y. M.; Tan, L. Y.; Chong, T. M.; Chan, K. G. Non-antibiotic quorum sensing inhibitors acting against N-acylhomoserine lactone synthase as druggable target. Sci. Rep. 2014, 4, 7245. (179) Yap, P. S. X.; Krishnan, T.; Yiap, B. C.; Hu, C. P.; Chan, K. G.; Lim, S. H. E. Membrane disruption and anti-quorum sensing effects of synergistic interaction between Lavandula angustifolia (lavender oil) in combination with antibiotic against plasmid-conferred multi-drugresistant Escherichia coli. J. Appl. Microbiol. 2014, 116, 1119−1128. (180) Yap, P. S.; Krishnan, T.; Chan, K. G.; Lim, S. H. Some evidences on the mode of action of Cinnamomum verum bark essential oil, alone and in combination with piperacillin against a multi-drug resistant Escherichia coli strain. J. Microbiol. Biotechnol. 2014, 2410.4014/jmb.1407.07054. (181) Koh, C. L.; Sam, C. K.; Yin, W. F.; Tan, L. Y.; Krishnan, T.; Chong, Y. M.; Chan, K. G. Plant-derived natural products as sources of anti-quorum sensing compounds. Sensors 2013, 13, 6217−6228. (182) van der Veen, S.; Abee, T. Bacterial SOS response: a food safety perspective. Curr. Opin. Biotechnol. 2011, 22, 136−142. (183) Gottschalk, S.; Ifrah, D.; Lerche, S.; Gottlieb, C. T.; Cohn, M. T.; Hiasa, H.; Hansen, P. R.; Gram, L.; Ingmer, H.; Thomsen, L. E. The antimicrobial lysine-peptoid hybrid LP5 inhibits DNA replication and induces the SOS response in Staphylococcus aureus. BMC Microbiol. 2013, 13, 192. (184) Juneja, V. K.; Gonzales-Barron, U.; Butler, F.; Yadav, A. S.; Friedman, M. Predictive thermal inactivation model for the combined effect of temperature, cinnamaldehyde and carvacrol on starvationstressed multiple Salmonella serotypes in ground chicken. Int. J. Food Microbiol. 2013, 165, 184−199. (185) Juneja, V. K.; Yadav, A. S.; Hwang, C.-A.; Sheen, S.; Mukhopadhyay, S.; Friedman, M. Kinetics of thermal destruction of Salmonella in ground chicken containing trans-cinnamaldehyde and carvacrol. J. Food Prot. 2012, 75, 289−296. (186) Heide, L. New aminocoumarin antibiotics as gyrase inhibitors. Int. J. Med. Microbiol. 2014, 304, 31−36. (187) Schroder, W.; Goerke, C.; Wolz, C. Opposing effects of aminocoumarins and fluoroquinolones on the SOS response and adaptability in Staphylococcus aureus. J. Antimicrob. Chemother. 2013, 68, 529−538.

(188) Cirz, R. T.; Jones, M. B.; Gingles, N. A.; Minogue, T. D.; Jarrahi, B.; Peterson, S. N.; Romesberg, F. E. Complete and SOSmediated response of Staphylococcus aureus to the antibiotic ciprofloxacin. J. Bacteriol. 2007, 189, 531−539. (189) Woźniak, D.; Dryś, A.; Matkowski, A. Antiradical and antioxidant activity of flavones from Scutellariae baicalensis radix. Nat. Prod. Res. 2014, DOI: 10.1080/14786419.2014.983920. (190) Marathe, S. A.; Kumar, R.; Ajitkumar, P.; Nagaraja, V.; Chakravortty, D. Curcumin reduces the antimicrobial activity of ciprofloxacin against Salmonella Typhimurium and Salmonella Typhi. J. Antimicrob. Chemother. 2013, 68, 139−152. (191) Ultee, A.; Kets, E. P.; Smid, E. J. Mechanisms of action of carvacrol on the food-borne pathogen Bacillus cereus. Appl. Environ. Microbiol. 1999, 65, 4606−4610 http://aem.asm.org/content/65/10/ 4606.long. (192) Sirk, T. W.; Brown, E. F.; Friedman, M.; Sum, A. K. Molecular binding of catechins to biomembranes: relationship to biological activity. J. Agric. Food Chem. 2009, 57, 6720−6728. (193) Sirk, T. W.; Brown, E. F.; Sum, A. K.; Friedman, M. Molecular dynamics study on the biophysical interactions of seven green tea catechins with lipid bilayers of cell membranes. J. Agric. Food Chem. 2008, 56, 7750−7758. (194) Sirk, T. W.; Friedman, M.; Brown, E. F. Molecular binding of black tea theaflavins to biological membranes: relationship to bioactivities. J. Agric. Food Chem. 2011, 59, 3780−3787. (195) Friedman, M. Antibacterial, antiviral, and antifungal properties of wines and winery byproducts in relation to their flavonoid content. J. Agric. Food Chem. 2014, 62, 6025−6042. (196) Finotti, E.; Bersani, E.; Friedman, M. Application of a functional mathematical index for antibacterial and anticarcinogenic effects of tea catechins. J. Agric. Food Chem. 2011, 59, 864−869. (197) Friedman, M.; Juneja, V. K. Review of antimicrobial and antioxidative activities of chitosans in food. J. Food Prot. 2010, 73, 1737−1761 http://www.ingentaconnect.com/content/iafp/jfp/2010/ 00000073/00000009/art00021. (198) Nowotarska, S. W.; Nowotarski, K. I.; Friedman, M.; Situ, C. Effect of structure on the interactions between five natural antimicrobial compounds and phospholipids of bacterial cell membrane on model monolayers. Molecules 2014, 19, 7497−7515. (199) Ultee, A.; Kets, E. P.; Alberda, M.; Hoekstra, F. A.; Smid, E. J. Adaptation of the food-borne pathogen Bacillus cereus to carvacrol. Arch. Microbiol. 2000, 174, 233−238. (200) Di Pasqua, R.; Betts, G.; Hoskins, N.; Edwards, M.; Ercolini, D.; Mauriello, G. Membrane toxicity of antimicrobial compounds from essential oils. J. Agric. Food Chem. 2007, 55, 4863−4870. (201) Luz Ida, S.; de Melo, A. N.; Bezerra, T. K.; Madruga, M. S.; Magnani, M.; de Souza, E. L. Sublethal amounts of Origanum vulgare L. essential oil and carvacrol cause injury and changes in membrane fatty acid of Salmonella Typhimurium cultivated in a meat broth. Foodborne Pathog. Dis. 2014, 11, 357−361. (202) Chan, A. C.; Ager, D.; Thompson, I. P. Resolving the mechanism of bacterial inhibition by plant secondary metabolites employing a combination of whole-cell biosensors. J. Microbiol. Methods 2013, 93, 209−217. (203) Ayari, S.; Dussault, D.; Millette, M.; Hamdi, M.; Lacroix, M. Response of Bacillus cereus to gamma-irradiation in combination with carvacrol or mild heat treatment. J. Agric. Food Chem. 2010, 58, 8217− 8224. (204) Ayari, S.; Dussault, D.; Hayouni, E.; Hamdi, M.; Lacroix, M. Radiation tolerance of Bacillus cereus pre-treated with carvacrol alone or in combination with nisin after exposure to single and multiple sublethal radiation treatment. Food Control 2013, 32, 693−701. (205) Shen, S.; Zhang, T.; Yuan, Y.; Lin, S.; Xu, J.; Ye, H. Effects of cinnamaldehyde on Escherichia coli and Staphylococcus aureus membrane. Food Control 2015, 47, 196−202. (206) Tang, W.; Zhang, H.; Wang, L.; Qian, H. Membrane-disruptive property of a novel antimicrobial peptide from anchovy (Engraulis japonicus) hydrolysate. Int. J. Food Sci. Technol. 2014, 49, 969−975. Q



Review

(207) Shah, S.; Stapleton, P. D.; Taylor, P. W. The polyphenol (−)-epicatechin gallate disrupts the secretion of virulence-related proteins by Staphylococcus aureus. Lett. Appl. Microbiol. 2008, 46, 181− 185. (208) Li, G.; Xu, Y.; Wang, X.; Zhang, B.; Shi, C.; Zhang, W.; Xia, X. Tannin-rich fraction from pomegranate rind damages membrane of Listeria monocytogenes. Foodborne Pathog. Dis. 2014, 11, 313−319. (209) Patil, S. D.; Sharma, R.; Srivastava, S.; Navani, N. K.; Pathania, R. Downregulation of yidC in Escherichia coli by antisense RNA expression results in sensitization to antibacterial essential oils eugenol and carvacrol. PLoS One 2013, 8, article e57370,10.1371/journal.pone.0057370 (210) Ait-Ouazzou, A.; Espina, L.; Gelaw, T. K.; De Lamo-Castellví, S.; Pagán, R.; García-Gonzalo, D. New insights in mechanisms of bacterial inactivation by carvacrol. J. Appl. Microbiol. 2013, 114, 173− 185. (211) Altintas, A.; Tabanca, N.; Tyihak, E.; Ott, P. G.; Moricz, A. M.; Mincsovics, E.; Wedge, D. E. Characterization of volatile constituents from Origanum onites and their antifungal and antibacterial activity. J. AOAC Int. 2013, 96, 1200−1208. (212) Nafisi, S.; Hajiakhoondi, A.; Yektadoost, A. Thymol and carvacrol binding to DNA: model for drug-DNA interaction. Biopolymers 2004, 74, 345−351. (213) Ferreira, S.; Silva, F.; Queiroz, J. A.; Oleastro, M.; Domingues, F. C. Resveratrol against Arcobacter butzleri and Arcobacter cryaerophilus: activity and effect on cellular functions. Int. J. Food Microbiol. 2014, 180, 62−68. (214) Chueca, B.; Pagán, R.; García-Gonzalo, D. Oxygenated monoterpenes citral and carvacrol cause oxidative damage in Escherichia coli without the involvement of tricarboxylic acid cycle and Fenton reaction. Int. J. Food Microbiol. 2014, 189, 126−131. (215) Desbois, A. P.; Smith, V. J. Antibacterial free fatty acids: activities, mechanisms of action and biotechnological potential. Appl. Microbiol. Biotechnol. 2010, 85, 1629−1642. (216) Bolla, J. M.; Alibert-Franco, S.; Handzlik, J.; Chevalier, J.; Mahamoud, A.; Boyer, G.; Kiec-Kononowicz, K.; Pages, J. M. Strategies for bypassing the membrane barrier in multidrug resistant Gram-negative bacteria. FEBS Lett. 2011, 585, 1682−1690. (217) Schweizer, H. P. Understanding efflux in Gram-negative bacteria: opportunities for drug discovery. Expert Opin. Drug Discovery 2012, 7, 633−642. (218) Kim, S. P.; Nam, S. H.; Friedman, M. Rice hull smoke extract protects mice against a Salmonella lipopolysaccharide-induced endotoxemia. J. Agric. Food Chem. 2014, 62, 7753−7759. (219) Kim, S. P.; Park, S. O.; Lee, S. J.; Nam, S. H.; Friedman, M. A polysaccharide isolated from the liquid culture of Lentinus edodes (shiitake) mushroom mycelia containing black rice bran protects mice against a Salmonella lipopolysaccharide-induced endotoxemia. J. Agric. Food Chem. 2013, 61, 10987−10994. (220) Friedman, M.; Rasooly, R. Review of the inhibition of biological activities of food-related selected toxins by natural compounds. Toxins 2013, 5, 743−775. (221) Rada, X.; Todd, J.; Friedman, M.; Patel, J.; Jaroni, D.; Ravishankar, S. Combining essential oils and olive extract for control of multi-drug resistant Salmonella enterica on organic leafy greens. Food Control 2015, submitted for publication. (222) Friedman, M.; Zhu, L.; Feinstein, Y.; Ravishankar, S. Carvacrol facilitates heat-induced inactivation of Escherichia coli O157:H7 and inhibits formation of heterocyclic amines in grilled ground beef patties. J. Agric. Food Chem. 2009, 57, 1848−1853. (223) Rounds, L.; Havens, C. M.; Feinstein, Y.; Friedman, M.; Ravishankar, S. Concentration-dependent inhibition of Escherichia coli O157:H7 and heterocyclic amines in heated ground beef patties by apple and olive extracts, onion powder and clove bud oil. Meat Sci. 2013, 94, 461−467.

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