Is Quorum Signaling by Mycotoxins a New Risk-Mitigating Strategy for

Review pubs.acs.org/JAFC

Is Quorum Signaling by Mycotoxins a New Risk-Mitigating Strategy for Bacterial Biocontrol of Fusarium verticillioides and Other Endophytic Fungal Species? Charles W. Bacon,* Dorothy M. Hinton, and Trevor R. Mitchell U.S. National Poultry Research Center, Toxicology & Mycotoxin Research Unit, Russell Research Center, Agricultural Research Service, U.S. Department of Agriculture, Athens, Georgia 30605, United States ABSTRACT: Bacterial endophytes are used as biocontrol organisms for plant pathogens such as the maize endophyte Fusarium verticillioides and its production of fumonisin mycotoxins. However, such applications are not always predictable and efficient. In this work, we hypothesize and review work that quorum sensing inhibitors are produced either by fungi or by pathogenic bacteria for competitive purposes, altering the efficiency of the biocontrol organisms. Recently, quorum sensing inhibitors have been isolated from several fungi, including Fusarium species, three of which are mycotoxins. Thus, we further postulate that other mycotoxins are inhibitors or quenching metabolites that prevent the protective abilities and activities of endophytic biocontrol bacteria within intercellular spaces. To test the aforementioned suppositions, we review work detailing the use of bioassay bacteria for several mycotoxins for quorum activity. We specifically focus on the quorum use of endophytic bacteria as biocontrols for mycotoxic fungal endophytes, such as the Fusarium species and the fumonisin mycotoxins. KEYWORDS: quorum sensing, quorum quenching, Fusarium, F. verticillioides, mycotoxins, fumonisins, endophytes, N-acyl homoserine lactone, AHL

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INTRODUCTION The literature review presented here focuses specifically on studies pertaining to the fusaria species that thrive within maize, such as Fusarium verticillioides (Sacc.) Nirenberg (synonym, F. moniliforme; teleomorph, Gibberella moniliformis; mating population A of the Gibberella fujikuroi species complex). This species and other members of this complex produce the fumonisin mycotoxins. The nature of toxicity resulting from consuming this mycotoxin has been extensively studied in the context of all species of livestock and poultry, although research has recently been extended to human toxicity as well. F. verticillioides is a common contaminant of most environments across the planet and, according to the available evidence, can infect over a hundred species of plants, most of which are agronomically important.1 In maize, this species produces the three analogues or fumonisins, as well as their isomers. Other metabolites include fusarin C and fusaric acid. Fusaric acid and its related metabolites seem to be particularly damaging when present in concentrations that are phytotoxic and or in concentrations that are required for mammalian toxicity, rather than the lesser plant physiological concentration.2−7 The fumonisins are produced by the majority of isolates of the F. verticillioides and its related species complex. This distinguishes it from other mycotoxic species such as those of the Aspergillus flavus/Aspergillus parasiticus complex, in which only a small percentage of isolates produce the aflatoxin mycotoxins. Furthermore, previously conducted surveys of fumonisinproducing strains within a Fusarium population indicate the widespread occurrence of these producing strains,2−7 suggesting that this class of mycotoxin serves an important biochemical function for the competitiveness of this fungus rather than serving strictly for herbivore protection. This article not subject to U.S. Copyright. Published 2016 by the American Chemical Society

Numerous post- and preharvest methods aimed at preventing the accumulation of the fumonisins and other fusaria mycotoxins in grains and other commodities have been proposed. In this context, the use of biocontrol agents is of particular importance for the present study, as several of these are endophytic bacteria and fungi. Endophytic fungi are well-known for their ability to produce structurally and biologically diverse novel compounds with a wide range of applications. Hundreds of metabolites display antibacterial and antifungal activities, and several classes of these have strong pharmacological applications. We postulate that host-produced compounds that modify behavior of endophytic microbes exist within the endophytic community, often reducing nutrient predations and suppressing pathogenic behaviors. These behavior-modifying compounds are proposed to include phenolic acids, a variety of nitrogenous bases, and indole compounds, likely along with other secondary metabolites that are interactive as inhibitors and stimulators for each symbiont.8−11 Recently, research on endophytism has extended to the concept of quorum sensing or cell density dependent gene regulation and its controls, which have been explored at the community and species levels of endophytic fungi of grasses.12 Quorum sensing is a mechanism of microbial communication that is driven by cell density and results in a cavalcade of cellular behaviors reflecting specific metabolic regulation. Quorum mechanisms are found in both Gram-negative and Gram-positive Special Issue: Public Health Perspectives of Mycotoxins in Food Received: Revised: Accepted: Published: 7071

August 30, 2016 November 29, 2016 December 1, 2016 December 1, 2016 DOI: 10.1021/acs.jafc.6b03861 J. Agric. Food Chem. 2017, 65, 7071−7080

Journal of Agricultural and Food Chemistry

Review

The focus of this review is on a specific class of fungal secondary metabolites, the mycotoxins that are suspected of having inhibitory, mimicking, or autoinducing activity through quenching or quorum degradation via the production of specific enzymes. In particular, research on the concept of quorum inhibiting or quenching is discussed, along with the pertinent studies on its diversity among fungi and the identity of wellknown mycotoxins with possibility of quorum activities. We also review available work based on using quorum inhibiting activity, because this aspect is of particular interest for the development of agronomic biocontrol strategies utilizing endophytic bacteria.

bacteria and are accomplished by the production and sensing of small highly diffusible molecules produced within the colony by cells when population density reaches some critical level. These signaling molecules are highly specific and structurally varied. Because the focus of this review is on plant pathogens and their control, in this context, quorum sensing relates directly to the regulation and secretion of virulence factors and toxin or secondary metabolite production. In addition to bacteria, quorum activities have recently been discovered in fungi and higher organisms, suggesting its importance in evolution. Quorum sensing was first discovered in Aliivibrio fisheri, a bioluminescent bacterium that is a mutualist with the bobtail squid. However, they produce luciferase and the resulting luminescence in concentrated populations only.13 The importance of this quorum activity was extensively studied in relation to cell density effects, leading to its subsequent discovery in other bacterial species.14−16 Quorum sensing and inhibition have recently attracted considerable research interest due to their importance in fungi and other multicellular organisms.12,15,17 In this work, however, we postulate that fungi, like bacteria, use quorum regulation to maintain or alter population-level behaviors, including symptomless infections, pathological and morphological expressions, and reproductive challenges, such as sporulation, spore dormancy, and germination. Density dependence is central to the mechanism of quorum sensing.13,18 Because cell density is a prerequisite for quorum sensing, it is usually associated with morphological structures such as biofilms, which may be substituted by other structures where endophytes are in close associations, such as the intercellular spaces of plant. Empirical evidence indicates that endophytic bacteria occupy such spaces in large quantities, and this formation has been observed along the entire plant axis.19 As quorum sensing is critical to several aspects of cellular behavior, such as toxin production, sporulation, and morphological development, it has been the subject of several reviews.8,13,14,16,20−24 Quorum sensing is also affected by environmental influences resulting in nutrient acquisition and the synthesis of secondary stressrelieving and -deterring metabolites.20,25 In sum, quorum sensing is a competitive system that assists in the survival and communication of organisms. In this work, we propose that coordinated regulatory signaling between host and endophytes takes place within any endophytic species population.8,9,26 Furthermore, within a particular host, there are many endophytic species that are in direct competition. One aspect of quorum sensing pertains to its inhibition or quenching.27 The metabolites that act as quorum inhibitors are abundant and can potentially play a valuable role in the survival of pathogenic species. As facultative endophytes, the fusaria are also capable of living as saprophytes, making their control difficult, as they thrive on dying and dead plant matter. As this category of endophytes has not been as extensively studied as the obligate endophytes of grasses were, the information concerning their control is limited and does not extend to the endophytic alternative lifestyle. Recently, three mycotoxins have been shown to inhibit quorum sensing mechanisms.28,29 In the context of the present work, focusing specifically on fungal endophytes, it is particularly important to establish how widespread quorum sensing in fungi is, as well as elucidate the quorum activities by other mycotoxins. Studies on quorum sensing are facilitated by bacterial biosensor systems that have been developed along with associated mechanisms to define and recognize quorum inducing and inhibiting metabolites in other organisms.

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DETECTION AND CHARACTERIZATION OF QUORUM METABOLITES To detect quorum inhibiting or quenching mechanisms, quorum signaling and quenching must be first analyzed, ideally using biosensor bacteria. As these bacteria are very sensitive to signaling and quenching, they can detect signals at physiological concentrations below the nanomole range. Their detection limits have been discussed.32 However, analytical methods based on their use do not allow quantitation and, thus, produce results that are reported as confidence intervals. To alleviate this issue, an authentic quorum signaling system must consist of cognate signal receptors and regulators, along with specific genes that are expressed in a population-dependent manner. Although this is considered the definition of quorum signaling,30 biosensor activity is usually determined on the basis of measurements of specific bacterial properties. More specifically, when bacteria do not inhibit a signaling molecule they secrete, which results in a large number of such signaling molecules, this leads to quorum activity, thus allowing it to be measured indirectly. Although signaling molecules are usually specific to particular bacteria, the well-characterized N-acyl homoserine lactones (AHLs) (Figure 1) are typically found in Gram-negative bacteria, whereas some Gram-positive bacteria use small peptides and derivatives such as the cyclic dipeptides.31,32 Other bacterial species rely on different types of compounds to control population densities, such as butyrolactones, cyclic dipeptides, and bradyoxetin, and oligopeptides are used in a few Grampositive bacteria. Some signaling compounds, such as the

Figure 1. Structure of quorum sensors: N-acyl homoserine lactone (AHL), 1, from a Gram-negative bacterium, as an example of very active synthetic quorum inducers; N-(3-oxohexanoyl)-L-homoserine lactone, where R = CH3(CH2)COCH2. AIP-1, 2, as an example of cyclic peptide signaling molecule from a Gram-positive bacterium. 7072

DOI: 10.1021/acs.jafc.6b03861 J. Agric. Food Chem. 2017, 65, 7071−7080


Review

Table 1. Typical Strains Used To Screen for Quorum Signaling and Quenching Activities35,a strainb

purpose

Chromobacterium violaceum ATCC 12472 C. violaceum ATCC 31532 C. violaceum CV026 Pseudomonas chloraraphis (aureofaciens)b 30−84 Pseudomonas aeruginosa PA01 Pseudomonas putida pA5-C8 Agrobacterium tumefaciens 12472 A. tumefaciens NTL4 (pCF218) (jpCF372) A. tumefaciens A136 (pCF218) (pCF372) A. tumefaciens KYC6 A. tumefaciens KYC55 (pJZ372) (pJZ384) (pJZ410) Escherichia coli JM109 Vibrio harveyi BB170 Serratia marscesensb

AHSL biosensor and wild type; used to detect QSI (quorum sensing inhibitors) by loss of pigments a C6-HSL overproducer that can detect either C4- or C6-HSLs used to detect either C4- or C6-HSLs QSI indicator and type strain positive control for QSI for C. violaceum 12472 as it produces both C4- and 3-oxo-C12-HSLs ASI use to detect C8-HSLs QSI indicator strain; wild type used to detect a range of AHLs biosensor for range of acyl HSLs positive control for acyl HSL assay, an overproducer of 3-oxo-C8 HSL for detection of acyl HSLs type quorum alternate highly sensitive biosensing strain used to detect C8-HSLs AI-2 quorum signals used to detect C8-HSLs

a

All bacteria were obtained from Dr. Robert McLean, Department of Biology, Texas State UniversitySan Marcos, TX, USA, and are designed for specific uses.35,36 Abbreviations: AI-2, autoinducer 2; AHLs, N-acylhomoserine lactones; 3-oxo-C6- or C12-HSLs, N-3-oxo-hexanoyl homoserine lactone; HSLs, homoserine lactones. bOther strains that produce pigments in response to quorum sensing bioassays.

bacteria can be identified by the traditional chemical analyses, such as gas chromatography, HPLC, and mass spectrometric analyses, or a combination of these. Some authors have reported employing TLC based on biosensor bacteria to identify known or unknown separated compounds.40,41 However, these approaches must still be combined with those based on biosensor bacteria, as they are usually more sensitive than the instrumental methods.40,41,45

furanones, are characteristic of both Gram-positive and Gramnegative bacteria. However, as will be discussed below, an Australian alga, Delisea pulchra, utilizes a specific furanone as a quorum sensing inhibitor, suggesting not only use specificity but also complexity. Biosensor Bacteria. The common bacteria used for detecting either quorum quenching or quorum signaling are presented in Table 1. In these biosensing bacteria, quorum sensing is constitutively expressed by the production of specific signaling molecules, as well as having specific receptors that detect these signaling molecules. These biosensor strains have strict cultural and storage requirements, as well as media affinities, that must be respected in experimental studies and practical usage.33,35,36 A commonly used bioassay species is A. tumefaciens A136 (pCF218) (pCF372), synonym WCF47 (pCF218) (pCF372), which requires supplementation of culture media with βgalactosidase substrate such as X-gal to visualize any acyl HSL activity.35 However, several species, such as Pseudomonas chloraraphis (aureofaciens), Serratia marscesens, Pseudomonas aureofaciens, and Chromobacterium violaceum, produce their natural pigments in response to quorum sensing. The commonly used pigmented species for quorum inhibition is the wild type strain C. violaceum 12472, the quorum sensing of which is inhibited by the lack of production of the deep violet pigment violacein. Some nonpigmented mutant strains of this wild type are utilized to substantiate aspects of quorum inhibition, including their use as experimental controls depending on the design of an experiment. P. chloraraphis is another popular pigmented species that produces a yellow pigment. Several authors have reported the application of plant and fungal extracts, as well as whole organisms such as bacteria and plants, for screening quorum inducing and inhibiting sensing.26,32−37 Other procedures have been developed for identifying quorum activity in ecological materials such as extracts, sediment, liquid and gaseous environments, and gene expression measurements in vivo and in vitro.38,39 At present, several procedures also exist for identifying genes controlled by quorum sensing, and methods for measuring gene expression within cells have also been reported.18,32,40−45 Chemical Characterization. The chemical identities of suspect quorum metabolites distinguished using the biosensor

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QUORUM SENSING AND QUENCHING ACTIVITIES FROM PLANT METABOLITES The cell-to-cell communication discussed above enables the coordination of several essential activities and behaviors within a population density by altering gene expression. This is accomplished by the production and release of signaling molecules that are characterized by great structural diversity. Most can be classified into chemical types, namely, N-acyl homoserine lactones (AHLs), referred to as autoinducer-1, characteristic of Gram-negative bacteria; and autoinducer-2 (AI2).36,39 However, it should be noted that other chemically different compounds are produced by these and other microorganisms, along with molecules that are able to antagonize or inhibit quorum metabolites. Plant Quorum Metabolites. As microbial endophytes develop close associations with their host, it is important to elucidate the contributions of each to the final expression of quenching or sensing by metabolites. This, however, requires identification of vascular plants producing quorum regulating compounds. The results yielded by two screenings focusing on vascular plants indicate that they are capable of producing quorum metabolites.10,29 Several natural products generated by most plants act as a protection against quorum metabolites, which in some associations results in plant resistance to pathogens. However, to date only a few quorum metabolites from plants have been structurally determined, and most of the research conducted in this field has focused on quorum quenching compounds.10,29,46−49 For example, the flavanone compound naringin, a glycosylated flavonoid, was shown to be one of the active compounds in orange extract that were inhibitory to quorum sensing effects.49 In the red marine seaweed Delisea pulchra, halogenated furanones inhibit several components of the quorum systems preventing bacteria from colonizing 7073



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the seaweed.50 Grapefruit extracts are also inhibitory to quorum activity posited to be due to furocoumarins, limonoids, pectin, and several unidentified components.51,52 Other quorum plant metabolites that have been identified thus far include the phenolic-derived malabaricone C from nutmeg and a powerful isothiocyanate,46,53 sulforaphane, and quercetin found in broccoli.10 The plants of interest for the present investigation, namely, maize, as well as grasses in general, have not been thoroughly examined for quorum activity. Grasses are well-known for their biosynthetic inability to produce secondary metabolites, but have achieved this function over time by cohabitating with microbial endophytes. The endophyte produces metabolites that serve to protect and alleviate biotic and abiotic stresses. Indeed, the close associations of grasses with endophytic microorganisms that are rich in the variety of secondary metabolites produced have been presented as a driving evolutionary strategy for the symbiotic and mutualistic associations in plants in general. Thus, it is likely that the quorum activity control in maize and other plants relates to the production of degrading enzymes, as discussed below, although it can also stem from inactivating metabolites with a dual function, such as salicylic acid, indoleacetic acid, and γaminobutyric acid. Plant Quorum Mimics. Some higher and lower plants produce compounds that mimic quorum sensing signals, interfering with processes.22,46 Other plants rely on common metabolites exhibiting multiple functions, such as salicylic acid that, when present in very small amounts, is a regulating plant defense compound. However, it is also considered effective in down-regulating pathogenic attachments and other factors.54 Other plant metabolites, although structurally similar to quorum signals, possess quenching activity in one or several sensing systems.55 Some of the most potent inhibitors of quorum sensing compounds include N-(heptylsulfanylacetyl)-L-homoserine lactone and 4-nitro-pyridine-N-oxide. However, other potent but unidentified compounds have been isolated from extracts of garlic.29 The halogenated furanones, L-canavanine, and cinnamaldehyde also exhibit quorum inhibition activity. Many more plant and higher organism metabolites have been detected, although their structures have not been determined. 11 Furthermore, regulation of the mimic signal metabolites is based on accumulation and secretion patterns, which determine how and when plants respond to specific mimics that target quorum sensing disruption in bacteria. Enzymatic Degradations. The in planta degradation of quorum metabolites by competing endophytic microbes, such as bacteria and Fusarium species, is likely characteristic of specific plant hosts. This assertion is made due to the complex existence of phytoanticipins found in maize and other cereals.56,57 For example, a class of hydroxamic acids, which consists of two benzoxazinoids that are present in corn, serve as the early defense system for corn seedling against insects and fungal pathogens. This class further includes 2,4-dihydroxy-7-methoxy-2H-1,4benzoxazin-3(4H)-one (DIMBOA) and 2-hydroxy-4,7-dimethoxybenzoxazin-3-one (DIBOA). Both are very effective antimicrobial compounds, but apparently do not act as quenchers.58 Nonetheless, both are readily degraded by F. verticillioides and Bacillus mojavensis into products that may be highly active,59 perhaps as quenchers. Furthermore, the potency of both DIMBOA and DIBOA is very high, whereby even very small concentrations are sufficient to limit transformation in corn and other cereal monocots, which is a process that relies on signaling.58 Available evidence indicates that

enzymes that degrade signals also occur in the rhizosphere,60 even though these soil enzymes presumably originate from bacteria. Transgene studies indicate that quorum sensing degrading enzymes are present in plant hosts, indicating that such studies might serve as foci of biocontrols of pathogenic organisms.57 We further postulate that they might also control some of the more symptomless fusaria infections, reducing their mycotoxin content. Finally, the degradation of AHLs and related compounds has been shown to occur in roots endophytically infected with certain fungi.55

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FUNGI AND MYCOTOXINS: QUORUM SENSING AND QUENCHING ACTIVITIES? Quorum sensing was first observed in the marine bacterium Vibrio harveyi in 1973, referred to as autoinduction, and in 1977, the chemical signal was discovered in the related organism V. fischeri. These discoveries have promoted extensive research in this field, which has resulted in thousands of reports on this phenomenon in several bacteria and higher organisms, primarily as a social system of communications between bacteria. The regulation of virulence factors by this mechanism has attracted the attention of mycologists, who initially demonstrated this effect in a yeast species, Candida albicans. Subsequent studies have resulted in the identification of several species of human pathogenic yeast, suggesting the existence of quorum sensing in fungi (Tables 2 and 3).61−66 Table 2. Fungal Species Tested for Quorum Sensing or Inhibiting Activity fungi Penicillium expansum, P. hirsutum, P. italicum, P. olsonii, P. roqueforti a Fusarium graminearum,aF. sporotrichioides,bF. oxysporum and 21 other species known to produce fusaric acid74 Candida albicans Histoplasma capsulatum Ceratocystis ulmi Saccharomyces cerevisiae Crytococcus neoformans Neurospora crassa Aspergillus f lavus,a A. nidulans Auricularia auricular Tremella f uciformis Lasidiplodia sp.

quorum sensing

quorum inhibiting

68

+

17, 60, 65

+ + + + + + + + + +

reference

+

43, 62 43, 62 43, 62 62 43, 62 62 26 42 42 64

a

Denotes species known to produce mycotoxins. bThere are 21 other Fusarium species also known to produce fusaric acid;74 therefore, this number is expected to increase, reflecting the universal occurrence within the genus and its effect on quorum activity.

Fungal Quorum Inducers. A density-dependent and quorum sensing-like activity, as well as related molecules, necessary for specific signaling-dependent functions, has been detected in Aspergillus flavus and its mutants during the morphological changes from sclerotia to conidial development.67 Derivatives of multicolic acid have been proposed as quorum sensing molecules in the fungi Penicillium sclerotiorum68 and A. terreus.69 Although a universal autoinducer has not yet been identified in fungi, findings yielded by several studies indicate that the oxylipins, 3,7,11-trimethyldodeca-2,6,10-trien-1-ol, commonly called farnesol, might be very common in yeast and 7074



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Table 3. Quorum Sensing Inhibition by Mycotoxins Measured with Chromobacterium violaceum 1247279 fungus

mycotoxin

Aspergillus f lavus/A. parasiticus Alternaria spp.

aflatoxin B1 alternariol

Citrinin Penicillium spp., Aspergillus flavus, and A. versicolor

citrinin cyclopiazonic acid

Aspergillus ochraceus, A. carbonarius, and Penicillium verrucosum Penicillium spp. and A. ochraceus Fusarium species

ochratoxin A

Fusarium species Fusarium species Aspergillus spp., Penicillium spp., and Byssochlamys spp.

quorum activity (ref)

mammalian toxicity hepatic necrosis, cirrhosis, or carcinoma of the liver cytotoxic, fetotoxic, teratogenic mutagenic, and genotoxic nephrotoxic, hepatotoxic, and cytotoxic effects sarcoplasmic reticulum inhibitor, and toxic in high dosages carcinogenic, hapatotoxicity, and neurotoxicity

penicillic acid fusaric acid zearalenone fumonisins (mixture of B1 and B2 analogues) patulin

NDa,b NDb inhibitorb NDb NDb

antibiotic and carcinogenic activities inhibitory to cell proliferation, DNA synthesis, and phytotoxic infertility, abortion, and sexual disorders hepatotoxic and nephrotoxic

inhibitor17 inhibitor80

genotoxic

inhibitor17

inhibitorb inhibitorb

a

ND, no inhibition of violaceum production detected compared to controls. bThese mycotoxins were obtained from Romer Laboratories (St. Louis, MO, USA); the inhibitory mycotoxins citrinin, zearalenone, and fumonisin had purities of 99.6, 99.7, and 98.3%, respectively. Purities of others ranged from 99.9 to 98.7%. All mycotoxins were in solutions of acetonitrile, whereby appropriate amounts were placed in 96-well microtiter plates, and the acetonitrile was evaporated over an 8 h period under a hood. The resulting residue was taken up in 0.1 mL of Luria−Bertani (LB) medium, and each well received 0.1 mL of inoculum, diluted to 1:100 ratio with LB medium, from an overnight culture of Chromobacterium violaceum ATCC 12472. The inhibition of violacein production in a well of each treatment group was based on 48−72 h cultures of the bacterium incubated at 30 °C following the modified procedure of McLean et al.36 Each well received 5 nM of each mycotoxin. Control groups consisted of LB medium and bacterium and acetonitrile (unpublished results).

creeper, Ventilago madraspatana, an Asian vine with some medicinal applications, which is also employed in the tannin and dying industry, have been determined. 79 Although 15 endophytes have been isolated, only F. graminearum and Lasidiplodia sp. exhibited high quorum inhibiting activity in the C. violaceum test.79 F. graminearum is the producer of the mycotoxins deoxynivalenol, zearalenone, and zearalanone, and the quorum activities of these mycotoxins are discussed below. Quorum sensing inhibitory activity to C. violaceum CV026 has also been identified in extracts of unknown endophytic marine species of Fusarium, Sarocladium, Epicoccum, and Khuskia.80 These species were isolated from coral reefs off the coast of Mexico, and no quorum compounds were chemically identified by the authors. To date, quorum quenching or inhibiting have been studied more extensively than signaling, given their greater relevance for practical applications of biocontrol relative to the actual mechanisms of sensing. Quenchers can serve the purpose of designer metabolites that are highly useful for fungicidal or bactericidal applications. Quorum sensing inhibitors have been demonstrated in Penicillium species,15,17,65 which include the mycotoxins penicillic acid, fusaric acid, and patulin.17,73 Therefore, other species of fungi that produce these metabolites15,17,65 should also show quorum activity. Similarly, because most Fusarium species produce fusaric acid,74−76 quorum quenching activity in this one genus includes numerous species, reflecting common synthesis by them. It is thus posited that quorum quenching may be widespread in some genera of fungi. There are also chemical modifications of fusaric acid by the endophytic state of one species, F. oxysporum.77 The activities of fusaric acid may be either increased, decreased, or completely altered to act as a quorum inducer rather than quencher. A recent survey of 25 Penicillium species for quorum activity included 6 mycotoxic species, the extracts of which produced quorum sensing inhibitors (Table 1).17 The mycotoxins potentially produced by these Penicillium species include citrinin,

other fungi. The oxylipins are a group of oxygenated polyunsaturated fatty acids that function as inter- and extracellular signals in higher organisms. Owing to their structural diversity, they exhibit functions not only in quorum sensing but also in sexual development and cell aggregation sporulation processes, among many others.34,66 Oxylipins associated with a variety of fungi, including A. flavus, have been reported in the literature, and Tsitsigiannis and Keller66 examined those found in plants and reviewed their role as sensing metabolites. Greater understanding of the effects of this metabolite has prompted research focusing on A. flavus, as well as its production of the mycotoxin aflatoxin, although most of the studies are based on the related and useful model of A. nidulans.26,70 Knowledge related to oxylipins is relevant for the process of aflatoxin accumulation, given that the densitydependent nature of quorum sensing in a higher mycelial fungus is of considerable agricultural importance.26 The synthesis of sterigmatocystin, a precursor to aflatoxin, and the antibiotic penicillin has also been shown to be stimulated by oxylipins.70 Oxylipins and related quorum sensing metabolites appear to be chemically similar to multicolic acid and other related compounds.62,63 Farnesoic acid and tyrosol have also been studied and have been shown to be equally effective as signaling molecules.71 The occurrence of farnesol and other oxylipins provides strong but indirect evidence for the existence of quorum sensing in fungi, including Histoplasma capsulatum, Ceratocystis ulmi, Saccharomyces cerevisiae, Crytococcus neoformans, Gaeumannomyce sp., Ustilago maydis, Penicillium spp., Fusarium spp., Pleurotus sp., Leptomitus sp., Achlya sp., Saprolegnia sp., Mucor spp., Aspergillus spp., Dipodascopsis sp., and Neurospora crassa.61,72 The widespread presence of oxylipins suggests that this might be a common family of signaling metabolites in fungi. Fungal Quorum Inhibitor and Mycotoxins. Quorum activities in fungal endophytes have been determined from only a limited number of hosts, and studies of quorum activity from fungal endophytes are particularly scarce. The endophytes of red 7075



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Figure 2. Structures of some quorum inhibiting mycotoxins. Fumonisin was tested as an equimolar mixture of fumonisins B1 and B2.

Figure 2. Such marked structural differences and activity relationships suggest that the substance might be a quorum sensing metabolite, because some signals at high concentrations can have an antibiotic effect either on competing organisms or on the host, as exemplified by farnesol.65,83 Using the biosensor bacterium for AHL quenching activity or inactivating processes, we present some of our unpublished data (Table 3) indicating that, in addition to patulin, penicillic acid, and fusaric acid,29 other mycotoxins were tested for quorum inhibitory activity. The additional mycotoxins selected represented agronomically important toxins, and the tabulated results are based on the ability of the bacterium C. violaceum ATCC 12472 to produce the violacein pigment when grown following the procedure of McLean et al.36 using 5 nmol of each mycotoxin (Table 3). The results pertain to three replicated cultures, repeated twice, whereby the percentage purity of each mycotoxin varied from 98.25 to 99.7%. None of the mycotoxins at the concentration used inhibited the growth of the test bacterium (data not shown), which is the key requirement for quorum metabolites. Three of the mycotoxins tested, namely, citrinin, zearalenone, and an equimolar mixture of fumonisins B1 and B2, were inhibitory to the C. violaceum bioassay (Table 3). Another group of mycotoxins, the diketopiperazines, has not been previously tested for quorum activity. However, some mycotoxins exhibiting a close structural similarity to diketopiperazines have been isolated from plants that have been identified as possessing quorum signaling activities.84 Thus, the mycotoxins gliotoxin, roquefortines C and E, and macrophominol are included in the diketopiperazines. However, it is essential to note that the similaritt and diversity of structures of these mycotoxins

cyclopiazonic acid, penicillic acid, chaetoglobosin, viridicatins, citreoviridin, patulin, mycophenolic acid, roquefortine C, penitrems A−F, and thomitrems A and E.78 With the exceptions of patulin and penicillic acid, the identity of additional mycotoxins responsible for the quorum inhibitions observed has not been determined. Other fungi that have been reported as having quorum sensing inhibitors, defined by the decrease in the production of violacein pigment in C. violaceum as described above, are listed in Table 1. Some of these are well-known mycotoxin producers, although most of the well-known quorum producing fungi are primarily pathogenic yeast species (Table 2). Mycotoxins as Quorum Inhibitors. Penicillic acid and patulin were the first mycotoxins established as quorum sensing inhibitors using the C. violaceum biosensor test. Although penicillic acid is bactericidal, it did not affect the growth rate of the biosensor organisms, as the quorum inhibiting effects were a thousand-fold lower than those obtained for the bactericidal activity.17 Fusaric acid exhibits phytotoxic properties in high concentrations but has similar quorum inhibitory signaling activity on AHLs produced by the biocontrol bacterium Pseudomonas chlororaphis, used to control fusaria pathogens. In addition, in higher concentrations, it was shown to repress the production of the antifungal metabolite phenazine-1-carboxamine.81,82 Thus, when plants are infected with the fusaria, the production of fusaric acid during the infection suggests that the failure of both Gram-positive and Gram-negative biocontrol bacteria might be due to the combined antibiotic effect and quorum quenching activity exhibited by competing organisms as well as the host plant.82 Several mycotoxins have been tested for quorum inhibition, and their diverse structures are depicted in 7076



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fungi has been conducted. Using bacteria as the model, some parallels with fungi have been proposed, allowing some analogies to be made. The signaling process is interactive and complex, because it occurs both within and between species, indicating the importance of quorum sensing compounds as modulators of microbe−plant interactions.88−92 However, whereas some degree of biocontrol specificity might be required in this process, there is very little evidence that such specificity exists. Signaling and/or host recognitions are interactions that likely determine the success or failure of biological controls based on endophytes. Observing and analyzing interactions under field conditions is difficult, because the host plant endophytic microbiome consists of a variety of interacting microbes, ranging from viruses to fungi, and of which are biotrophs. If mycotoxins have a dual role of mammalian toxicity and quorum quenching, the biocontrol bacteria utilized as its target in planta must have a means of overcoming quenching to prevent accumulation of mycotoxins. If this hypothesis is valid, biocontrol agent usage in practical applications is even more complex than presently understood, as it also requires consideration of quenching activity.

shown in Figure 2 are not indicative or predictive of inhibitory quenching activity observed by the three mycotoxins citrinin, zearalenone, and the fumonisins (Table 3). Inhibitory activities of aflatoxin B1, alternariol, cyclopiazonic acid, and ochratoxin A were not observed in this test using C. violaceum. Additional tests with other biomarker strains and species should be tried. A more extensive test using additional concentrations of these and other mycotoxins, along with assays using the companion mutants of C. violaceum, described in Table 1, might yield valuable information on additional activity, such as quorum inducing activity of those scoring negative as inhibitors.

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QUORUM QUENCHING MECHANISMS FOR AGRICULTURAL AND BIOTECHNOLOGICAL APPLICATIONS Biological controls employing endophytes are highly desirable due to the uniqueness of the endophytic habit. However, successful endophytic microbe control is presently hindered due to the presence of at least two issues, namely, lack of appropriate management of the biocontrol agent in diverse environments, both externally and internally, and the inability of the biocontrol agent to colonize and protect the host throughout its growth cycle, culminating in the harvest of the host. Quorum sensors produced by competing pathogenic and nonpathogenic microbes have the potential to mitigate both of these concerns. In most instances, such endophytic microbes have been shown to produce a variety of metabolites that express in planta activity.85−87 The assumption that endophytes can control pathogens via the production of specific metabolites lacks empirical support; nonetheless, this hypothesis forms the basis for the development of some general concepts pertinent to host and endophyte associations.11 It is particularly noteworthy that no studies have been conducted to date on the signaling between host and microbe, confirming the need for the production of metabolites, such as antibiotics, when needed, by the host. Quorum Inhibiting Enzymes. Considerable research on two general and naturally occurring quorum quenching or inhibiting enzymes isolated from bacteria and eukaryotes has been conducted, and the findings yielded may lead to the development of transgenic approaches. These enzymes belong to the family of well-characterized quorum sensing degrading enzymes, the N-acyl homoserine lactone lactonohydrolases.57 In addition to lactonases, oxidoreductases and paraoxonases have also attracted research interest recently.57 Expressions of these acyl homoserine lactonases regulate the expression of a range of important biological functions, such as virulence genes within their quorum sensing domain. Thus, in transgenic plants or biocontrol microbes, these acyl homoserine degrading enzymes quench the action of quenching signals, blocking pathogenicity and other functions of potential pathogens. Discovery of such novel quorum inhibitors or degradative enzymes indicates that the biocontrol microbes having physiological responses that rely on quorum activity could be further supported. This is a new challenge for investigating the roles of secondary metabolites in host organisms and their use for enhancing biocontrol organisms. Nutrients. In recent research, nutritional concerns of both the host and biocontrol agent have been explored, along with their effects on the pathogenic species. Nutrient acquisition by the biocontrol agent from its host is posited to involve complex regulation processes that rely on key metabolites within the microbiome. Communication is an important part of regulation and species. However, although it is relatively well understood in certain bacteria, no research on communication mechanisms in

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FUTURE PERSPECTIVES Mycotoxins are a unique group of quorum quenching molecules having physiological behavior which might resemble that exhibited by fusaric acid, penicillic acid, and patulin. These mycotoxins control or prevent quorum sensing expression of essential genes.17,35,43,80 Thus, if mycotoxin synthesis is to be controlled, this activity should be prevented. A program based on the release of AHLs not responding to specific mycotoxins and other metabolites is highly desired. Moreover, the release of excessive amounts of AHLs and other sensing metabolites must not be contingent on a cell density dependent system; that is, the buildup of cells should not be prerequisite for the production of quorum sensing molecules. However, timing of AHL production is expected to be critical for the overall biocontrol response. In particular, to realize fully the benefits from quorum methodology in practice, additional knowledge of control points is required, along with the means of increasing or producing quorum inducers within plants, which could potentially be achieved via the application of transgenic technology. In addition, the physiological roles, if any, of quorum stimulus by the fungus regarding in planta mycotoxin production must also be better understood. Furthermore, inhibitory or quenching systems based on AHLs or AIPs and similar quorum metabolites that are highly competitive with fungal pathogens and their mycotoxins are required. Finally, better understanding of the role of mycotoxins concerning the colonization and infection of plants is needed. An alternative approach might rely on the application of transgenic AHL mimic compounds for host plant transformations that will augment or restore biocontrol activity against mycotoxic-inhibited systems with the impact of overwhelming the fungus or pathogen. Such AHL transgenic plants might modify the behavior of pathogenic and or mycotoxic fungi by altering the performance of other bacteria within mixed populations. Furthermore, by producing AHL transgenic hosts, the need for a specific population density for an appropriate signaling response may be overcome. This development might also result in a constant production of AHL and its regulated behaviors. In addition, an early production of AHL might allow hosts to avoid infection, whereby the presence of AHL would be sufficient to prevent host colonization and mycotoxin synthesis. The production of synthetic AHL mimic compounds may prove 7077



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(2) Chulze, S. N.; Ramirez, M. L.; Pascale, M.; Visconti, A. Fumonisin production by, and mating populations of, Fusarium section Liseola isolates from maize in Argentina. Mycol. Res. 1998, 102, 141−144. (3) Desjardins, A. E.; Plattner, R. D.; Shackelford, D. D.; Leslie, J. F.; Nelson, P. E. Heritability of fumonisin B1 production in Gibberella f ujikuroi mating population A. Appl. Environ. Microbiol. 1992, 58, 2799− 2805. (4) Desjardins, A. E.; Plattner, R. D.; Nelson, P. E. Fumonisin production and other traits of Fusarium moniliforme strains from maize in northeast Mexico. Appl. Environ. Microbiol. 1994, 60, 1695−1697. (5) Desjardins, A. E.; Plattner, R. D.; Nelson, P. E. Production of fumonisin B1 and moniliformin by Gibberella f ujikuroi from rice from various geographic areas. Appl. Environ. Microbiol. 1997, 63, 1838−1842. (6) Leslie, J. F.; Plattner, R. D.; Desjardins, A. E.; Klittich, C. J. R. Fumonisin B1 production by strains from different mating populations of Gibberella f ujikuroi (Fusarium section Liseola). Phytopathology 1992, 82, 341−345. (7) Miller, J. D.; Savard, M. E.; Sibilia, A.; Rapior, S.; Hocking, A. D.; Pitt, J. I. Production of fumonisins and fusarins by Fusarium moniliforme from southeast Asia. Mycologia 1993, 85, 385−391. (8) Braeken, K.; Daniels, R.; Mdayizeye, M.; Vanderleyden, J.; Michiels, J. Quorum sensing in bacterial-plant interactions. In Molecular Mechanisms of Plant and Microbe Coexistence. Soil Biology; Nautiyal, C. S., Dion, J. P., Eds.; Springer-Verlag: Berlin, Germany, 2008; pp 265−289. (9) Rhome, R.; Del Poeta, M. Lipid signaling in pathogenic fungi. Annu. Rev. Microbiol. 2009, 63, 119−131. (10) Koh, C.-L.; Sam, C.-K.; Yin, W.-F.; Tan, L. Y.; Chong, Y. M.; Chang, K.-G. Plant derived natural products as sources of anti-quorum sensing compounds. Sensors 2013, 13, 6217−6228. (11) Gao, M.; Teplitski, M.; Robinson, J. B.; Bauer, W. D. Production of substances by Medicago truncatula that affect bacterial quorun sensing. Mol. Plant−Microbe Interact. 2003, 16, 827−834. (12) Bacon, C. W.; White, J. F., Jr. Functions, mechanisms and regulation of plant endophyte communities. Symbiosis 2016, 68, 87−98. (13) Nealson, K. H.; Platt, T. Bacterial bioluminescence: its control and ecological significance. Microbiol. Rev. 1979, 43, 469−518. (14) Newton, J. A.; Fray, R. G. Integration of environmental and hostderived signals with quorum sensing during plant-microbe interactions. Cell. Microbiol. 2004, 6, 213−224. (15) Rasmussen, T. B.; Givskov, M. Quorum sensing inhibitors: a bargain of effects. Microbiology 2006, 152, 895−904. (16) Uroz, S.; Dessaux, Y.; Oger, P. Quorum sensing and quorum quenching: the yin and yang of bacterial communication. ChemBioChem 2009, 10, 205−216. (17) Rasmussen, T. B.; Skindersoe, M. E.; Bjarnsholt, T.; Phipps, R. K.; Christensen, K. B.; Jensen, P. O.; Andersen, J. B.; Larsen, O. T.; Hentzer, M.; Hoiby, N.; Givskov, M. Identity and effects of quorum-sensing inhibitors produced by Penicillium species. Microbiology 2005, 151, 1325−1340. (18) Nealson, K. H.; Platt, T.; Hastings, J. W. Cellular control of the synthesis and activity of the bacterial luminescent system. J. Bacteriol. 1979, 104 (313), 322. (19) Bacon, C. W.; Hinton, D. M. Endophytic and biological control potential of Bacillus mojavensis and related species. Biol. Control 2002, 23, 274−284. (20) Horswill, A. R.; Stoodley, P.; Stewart, P. D.; Parsek, M. R. The effect of the chemical, biological and physical environment on quorum sensing in structured microbial communites. Anal. Bioanal. Chem. 2007, 387, 371−380. (21) Zhang, L. H. Quorum quenching and proactive host defense. Trends Plant Sci. 2003, 8, 238−244. (22) Williams, P. Quorum sensing, communication and cross-kingdom signalling in the bacterial world. Microbiology 2007, 153, 3923−3938. (23) Miller, M. B. Quorum sensing in bacteria. Annu. Rev. Microbiol. 2001, 55, 165−199. (24) Lerat, E.; Moran, N. A. Evolution of bacterial Luxl and LuxR quorum sensing regulators. Mol. Biol. Evol. 2004, 21, 903−913.

effective in deterring the fungus inhibitory activity exhibited by mycotoxins while also prohibiting fungal degradative enzymes from destroying quorum proteins. Current applications of quorum activity, and attempts to prevent both quenching and sensing, are based on their use for control of pathogens and mycotoxic fungi either indirectly with microbes or directly via transgenic techniques. However, for quorum sensing inhibitors to be useful, they must be tested for each anticipated use to ascertain their effectiveness.73 In other words, positive results in one context cannot be generalized to other mycotoxins. A class of bioactive proteins from the solanaceous plants has been shown to be active as quorum sensing inhibitors against the virulence of one plant pathogenic strain of P. aeruginosa, which can serve as a starting material for the development of novel plant transgene approaches.93 Evidence presented in this review suggests that quorum activities, and quorum quenching metabolites in particular, are important candidates for the successful control of pathogenic and mycotoxin organisms.95,96 As discussed in this work, although research on this subject is limited, available data indicate that endophytic microbes have the potential to affect a biocontrol endophytic microorganism’s performance via quorum sensing mechanisms. Further developments in this field require additional knowledge, but research reviewed in this work points to the likelihood of developing resistance to the use of quorum suppressing or inhibiting metabolites. Resistance to one quenching metabolite, furanone, was rapidly developed by several organisms due to the emergence of mutations.10,94 Nonetheless, the presently available information on quorum quenching and related activity is insufficient to understand fully the role that mycotoxins and other fungal compounds play in quorum communications. Still, empirical evidence does suggest that gaining such knowledge is vital for better biocontrol exploitation, as well as for more effective biotechnological uses of quorum mechanisms.

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AUTHOR INFORMATION

Corresponding Author

*(C.W.B.) Phone: (706) 546-3142. Fax: (706) 546-3116. Email: [email protected]. ORCID

Charles W. Bacon: 0000-0002-4116-0786 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to Robert J. C. McLean, Department of Biology, Texas State UniversitySan Marcos, San Marcos, TX, USA, for the cultures of the biosensor bacteria, as well as for the insightful discussions pertaining to their use and preservation. We recognize and express special thanks to Clay Fuqua, Department of Biology, Indiana University, Bloomington, IN, USA, for the two overproducer AHL strains of Agrobacterium tumefaciens he developed, while also acknowledging his generosity in supplying us with strains that are providing the thrust for our research in this area.

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REFERENCES

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