Antibacterial Compounds from Marine Bacteria, 2010â2015 - Journal

Review pubs.acs.org/jnp

Antibacterial Compounds from Marine Bacteria, 2010−2015 Claudia Schinke,*,† Thamires Martins,† Sonia C. N. Queiroz,‡ Itamar S. Melo,‡ and Felix G. R. Reyes† †

Department of Food Science, School of Food Engineering, University of Campinas, Campinas-SP, CEP 13083-862, Brazil Brazilian Agricultural Research Corporation, Rodovia SP-340 km 127.5, Jaguariúna-SP, CEP 13820-000, Brazil

‡

ABSTRACT: This review summarizes the reports on antibacterial compounds that have been obtained from marine-derived bacteria during the period 2010−2015. Over 50 active compounds were isolated during this period, most of which (69%) were obtained from Actinobacteria. Several compounds were already known, such as etamycin A (11) and nosiheptide (65), and new experiments with them showed some previously undetected antibacterial activities, highlighting the fact that known natural products may be an important source of new antibacterial leads. New broad-spectrum antibacterial compounds were reported with activity against antibiotic resistant Gram-positive and Gram-negative bacteria. Anthracimycin (33), kocurin (66), gageotetrins A−C (72−74), and gageomacrolactins 1−3 (86−88) are examples of compounds that display promising properties and could be leads to new antibiotics. A number of microbes produced mixtures of metabolites sharing similar chemical scaffolds, and structure−activity relationships are discussed.

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INTRODUCTION The Centers for Disease Control and Prevention estimated that there were approximately 23 000 deaths due to resistant bacterial infections in the USA in 2013.1 According to the World Health Organization (WHO),2 there were nearly half a million new victims of multidrug-resistant tuberculosis (MDR-TB) in 2013, and 100 countries reported cases of extensively drug-resistant tuberculosis (XDR-TB). The WHO also reported that last resort medicines, such as third-generation cephalosporins, have failed to cure cases of gonorrhea in 10 countries. In addition, an editorial by Rice3 in 2008 nominated a small group of bacteria that “escape the lethal action of antibiotics” as the “the ESKAPE bugs”Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter speciesand called attention to the threat of antibiotic-resistant Gram-negative bacteria. He noted that “the ESKAPE bugs are extraordinarily important, not only because they cause the lion’s share of nosocomial infections but also because they represent paradigms of pathogenesis, transmission, and resistance”. In 2010, the Infectious Diseases Society of America (IDSA) started the “10 × ’20 Initiative”, with the aim of developing a global venture for antibiotics research and development focused on launching 10 new antibacterial drugs that are effective and safe for systemic administration by 2020.4 Periodic updates on antibacterial compounds in clinical trial have been published.5,6 In the latest report, the authors voiced concern over the lack of advance in new drugs active against MDR Gramnegative infections. As noted in the above-mentioned reports, many standard medical procedures will prove to be futile if no efficient anti-infective treatment is available. The development of new antibiotics is among the core actions that will help fight these deadly infections. © 2017 American Chemical Society and American Society of Pharmacognosy

Toward the aim of discovering new molecules displaying antibacterial properties, researchers around the world have dedicated time and effort to looking for novel sources (animals, microbes, and plants) in varied environments, including thermal springs, Antarctica, caves, seas, and deserts, to mention a few, from which to draw antibiotic leads.7 For several decades, the marine environment has been drawing attention, as many new compounds showing potent antibacterial activities have been discovered from bacteria residing on or in molluscs, algae, sediments, water, and corals.8−10 Researchers are still investigating the associations that occur among microbes, their hosts, and the individuals of the community sharing that habitat. However, from results already obtained, it is becoming evident that these associations involve the sharing of complex chemical signals, depending on whether they are competitive11 or mutually advantageous.10,12 The purpose of these signaling molecules appears to be fighting off competitors by killing or hindering their settlement. These antagonist compounds, especially those displaying new chemical scaffolds, present a much desired opportunity to discover new antibiotics with which to confront multiresistant bacteria. As early as the 1940s and 1950s, marine bacteria were shown to produce antimicrobial compounds. The 1960s saw the first marine bacterial metabolites identified,13 and the 1970s saw their antibiotic properties reported.14 Reviews on antibacterial compounds obtained from marine-derived bacteria have been published since the 1990s.14−17 More recently, such reports have emphasized molecules against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE),18,19 peptides,9,20 and lanthipeptides,21 as well as Received: March 15, 2016 Published: March 31, 2017 1215

DOI: 10.1021/acs.jnatprod.6b00235 J. Nat. Prod. 2017, 80, 1215−1228

Journal of Natural Products

Review

Table 1. Class of Marine Bacteria from Which Antibacterial Compounds Were Reported during 2010−2015 class

total number of active compounds

new compounds

new compounds active against Gram-negative bacteria

known compounds with novel activity

Actinobacteria Bacilli Gammaproteobacteria total

36 12 4 52

27 12 3 42

7 12 3 22

9

compounds isolated from actinobacteria (covering 1999− 2009)22 or from diverse microorganisms encompassing several chemical classes.23 Due to the fast evolving number of works published yearly on the subject, we thought it important to review those published from 2010 to 2015. In the present review, only compounds displaying minimum inhibitory concentrations (MICs) less than or equal to 20 μg mL−1 were selected from the literature. This criterion is a compromise between the stringent end point recommended for Gram-positive (64 μg mL−1 (17, 18, and 20). Structure−activity analysis highlighted the importance of the C4″ and C3″ components (OMe and carbamoyl) of the novobiose along with the hydroxy at C5 of the hydroxybenzoate moiety for the inhibition of MRSA. Substitution with other moieties at these positions caused a complete loss of inhibitory activity.

Streptomyces sp. strain MS100061 isolated from a South China Sea sediment produced spirotetronates, the new lobophorin G (21), and the known lobophorins A (22) and B (23).31 Mycobacterium bovis BCG (Pasteur 1173P2) was highly sensitive to these lobophorins (MICs 0.8−1.5 μg mL−1); however, Mycobacterium tuberculosis H37Rv (ATCC27294) demanded higher MICs (16−32 μg mL−1). The compounds were also active against B. subtilis ATCC6663 (MICs 1.5−12 μg mL−1). Compounds 21−23 were ineffective against S. aureus ATCC29213, MRSA, and P. aeruginosa ATCC27853. Structure−activity analysis indicated the amide-saccharide moiety in 23 to be essential for mycobacteria inhibition. In addition, 21 and 22 differ only by the presence of an acetyl group in the latter, which does not influence antimycobacterial potency but greatly increases the activity against B. subtilis. According to the authors, this is the first report of the inhibition of M. bovis BCG and M. tuberculosis H37Rv by lobophorins. Lobophorins were also obtained from Streptomyces sp. strain 12A35, which was recovered from a deep sea sediment from the South China Sea.32 Bioassay-guided purification led to the isolation of new lobophorins H (24) and I (25) and the known lobophorin F (26) and 23. Compounds 24, similar to the positive control ampicillin, and 23 showed strong inhibition of B. subtilis CMCC63501 (MICs 1.6−3.1 μg mL−1). Compounds 24 and 26 exhibited limited activity against S. aureus ATCC29213 (MICs of 6.2−50 μg mL−1). Compound 25 displayed no activity, and none of the isolated compounds inhibited E. coli ATCC25922. According to the authors, the increase in the number of monosaccharide units attached to the spirotetronate skeleton (4 units in compound 24) increased the inhibitory activity, which indicated that the chain length influences the antibacterial potency of lobophorins by specifically interacting with the yet unknown biological target.

Streptomyces avermitilis strain MS449,33 recovered from a South China Sea sediment, produced chromopeptide lactones, the known actinomycin D (27), actinomycin X2 (28), and actinomycin X0β (29) in high concentrations. Pure compounds 27−29 were active against Mycobacterium bovis BCG (Pasteur 1173P2), with MICs of 0.2−0.5 μg mL−1, and Mycobacterium tuberculosis (MTB) H37Rv (ATCC27294) with MIC values between 1 and 8 μg mL−1. The authors report that wild S. avermitilis MS449 is the first strain to simultaneously produce high quantities of 27−29 under nonoptimized conditions (0.15, 1.92, and 1.77 mg mL−1, respectively). The authors note that, in contrast to 27, which is a well-known therapeutically used drug, MTB H37Rv was more susceptible to 28. Streptomyces sundarbansensis MS1/7, isolated from brown marine algae collected on the Bejaia coastline, Algeria, produced a new phaeochromycin analogue compound, 2-hydroxy-5-[(6hydroxy-4-oxo-4H-pyran-2-yl)methyl]-2-propylchroman-4-one (30), and the known phaeochromycin C (31) and phaeochromycin E (32).34,35 Pure compound 30 was bacteriostatic against MRSA ATCC43300 (MIC 2 μg mL−1) but not against S. aureus ATCC25923. E. coli ATCC25922 was also inhibited but at a higher concentration (MIC 16 μg mL−1). Compounds 31 and 32 were ineffective against the bacteria tested. According to the authors, the bacteriostatic activity against MRSA and failure to inhibit S. aureus ATCC25923 are similar to the activity of epicatechin gallate, a molecule that interferes with the genes that are selectively involved in oxacillin or methicillin resistance in S. aureus. This suggests that the anti-MRSA activity of compound 30 may be due to the inhibition of the production of the 1218



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improved the antibacterial activity of human cathelicidin, a family of antimicrobial polypeptides present in macrophages and polymorphonuclear leukocytes. The improved activity of cathelicidin persisted, despite a reduction in the bactericidal effect of 33 in the presence of 20% human serum. A rare hybrid terpenoid/polyketide biosynthetic pathway may be responsible for the production of meroterpenoids obtained from Streptomyces sp. strain SCSIO 10428 isolated from a Xieyang Island sediment sample, in Beihai, Guangxi Province, China.38 The compounds obtained included the new 4-dehydro4a-dechloronapyradiomycin A1 (34), 3-chloro-6,8-dihydroxy-8α-lapachone (35), 3-dechloro-3-bromonapyradiomycin A1 (36), and the known analogues napyradiomycins A1 (37), 18oxonapyradiomycin A1 (38), napyradiomycins B1 (39), B3 (40), and SR (41), and naphthomevalin (42). Tested against S. aureus ATCC29213, B. subtilis SCSIO BS01, and Bacillus thuringiensis SCSIO BT01, strong inhibition activities were displayed by 40 (MIC ≤ 0.5 μg mL−1) and 36 (MIC ≤ 1 μg mL−1) and to a lesser extent by compounds 37, 39, and 42 with MICs ≤ 2 μg mL−1. Compounds 34, 35, and 38 were weakly active against these bacteria (MICs 4−32 μg mL−1). None inhibited E. coli, and compound 41 showed no antibacterial activity. Structure−activity relationships revealed that oxidation at C-17 (38), the presence at C-10a of a linear 10-carbon monoterpenoid subunit (36 and 37), and a cyclized sixmembered ring (39 and 40) or 14-membered ring (41) had a strong impact on the antibacterial activity of these unusually halogenated meroterpenoids.

penicillin-binding proteins (PBP2′) involved in cell wall synthesis.

The structure of the polyketide anthracimycin (33) is unique in that it does not show similarity to any reported antibacterial natural products. The compound was obtained from Streptomyces strain CNH365, which was isolated from marine sediments collected in Santa Barbara, CA, USA.36 Compound 33 potently inhibited B. anthracis (strain UM23C1-1) with an MIC of 0.03 μg mL−1 in a microplate assay. Other bacteria that were sensitive to the compound were S. aureus ATCC13709, E. faecalis ATCC29212, and Streptococcus pneumoniae ATCC51916, with MICs between 0.06 and 0.25 μg mL−1. However, poor activity was detected against E. coli MCR106 imp, E. coli MG1655 tolC, H. inf luenzae ATCC 31517, H. inf luenzae ATCC31517 KO, Burkholderia thailandensis E264 KO, and P. aeruginosa PAO1 KO. The authors note that 33 provided a 90% survival rate at 10 mg kg−1 in MRSA intraperitoneally infected CD1 mice. The synthetic C-4 dichloro derivative displayed higher activity against the Gram-negative pathogens, suggesting that small structural changes in the molecule may lead to new antibacterial compounds. Another study on 33 also obtained from Streptomyces CNH36537 demonstrated that not only several MSSA and MRSA strains and vancomycin-resistant S. aureus (MIC ≤ 0.25 μg mL−1) but also Gram-negative M. catarrhalis (MIC 4 μg mL−1) were susceptible to the compound. However, other pathogens such as P. aeruginosa, K. pneumoniae, and A. baumannii were insensitive. Not only did it exhibit rapid killing kinetics, but the in vitro data suggested that 33 also affected MRSA at subMIC levels. Sub-MIC conditions slowed MRSA growth and

Streptomyces scopuliridis SCSIO ZJ46,39 isolated from a deepsea sediment from the South China Sea, produced cyclohexapeptides, including the new desotamides B−D (43−45) and the known desotamide A (46), cyclo-(-Trp-Gly-Asn-Ile-LeuLeu-). Compounds 43 and 46, in which the Trp moiety is preserved, displayed antibacterial activity against S. aureus ATCC29213, S. pneumoniae NCTC 7466, and clinical methicillin-resistant Staphylococcus epidermidis (MRSE) shhsE1 with MICs between 12 and 32 μg mL−1. However, no inhibition was detected against K. pneumoniae ATCC13883 and 1219



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MRSA shhs-A1. Compounds 44 and 45, in which the Trp is cleaved either by oxidation (44) or by the loss of a carbon (45), displayed no antibacterial activity against any pathogen tested. These findings highlight the necessity of the integrity of the Trp moiety for inhibitory activity. According to the authors, clues to the biosynthetic relationships among the four metabolites are provided by the higher proportion obtained of compound 46, with 43−45 being minor products. They speculate that postassembly line oxidation of the Trp in compound 46 by the Trp-2,3-dioxygenase of S. scopuliridis SCSIO ZJ46 generates compound 44, and compound 45 might be the result of NFK (Nformylkynurenine residue) deformylation in compound 44.

Isolated from marine sediment from Utonde, Equatorial Guinea, the Streptomyces zhaozhouensis strain CA185989 produced three new polycyclic tetramic acid macrolactams,40 including the new isoikarugamycin (47), 28-N-methylikarugamycin (48), and 30-oxo-28-N-methylikarugamycin (49). The bioactivities of compounds 47−49 were compared to that of known ikarugamycin (50). Compounds 47, 48, and 50 strongly inhibited MRSA (MICs 1−4 μg mL−1), whereas compound 49 was inactive (MIC 32−64 μg mL−1). None of the compounds inhibited E. coli even at 64 μg mL−1. Structure−activity analysis revealed that methylation of the nitrogen atom of the tetramic acid moiety, as in 48, had no impact on its antibacterial activity. However, the ethyl group side chain (C-16) is crucial for the bioactivity of this family of compounds. Its oxidation to a carbonyl, as in 49, severely decreased its antibacterial activity. New streptophenazines I (51), J (52), and K (53), along with other streptophenazines, were detected in culture extracts of Streptomyces sp. strain HB202 isolated from a sponge from the Baltic Sea.41 The antibacterial activities of compounds 51−53 were compared with those of streptophenazine G (54), which is a known representative of this class of molecules. Compounds 54 and 53 showed activity against B. subtilis (IC50 of 3.6 and 9.1 μg mL−1, respectively) and S. epidermidis (IC50 of 3.6 and 6.1 μg mL−1, respectively). Compounds 51 and 52 showed no bioactivity. The authors report that the UV chromatogram of an ethyl acetate extract of the culture broth from a single strain showed a large number of peaks that indicated the presence of more than 20 phenazine derivatives in a single fermentation. They commented that this biological derivatization, a common feature of microbially produced antibacterial agents, facilitates structure−function analysis without the need for chemical synthesis experiments. Streptomyces sp. was isolated from a marine sediment sample from Chuuk, Federated States of Micronesia, and produced new

glycosylated macrolactins A1 (55) and B1 (56) as well as the known surfactant lauramide diethanolamine (57).42 The three compounds inhibited B. subtillis, E. coli, P. aeruginosa, and S. aureus with MICs of 0.02−0.13 μg mL−1, but were not as potent as azithromycin. The chemical structure of the biologically active surfactant is unusual in nature and differs from known antimicrobial agents. This is the first report on its antibacterial activity. The weaker activity of 55 and 56 compared to the corresponding free −OH at C-7 is probably explained by the presence of the sugar at C-7 on both molecules. The authors, however, speculate that the higher solubility in polar solvents of sugar-containing macrolactins could be an advantage. New buanmycin (58) and buanquinone (59), pentacyclic xanthones, were obtained from Streptomyces cyaneus isolated from a tidal mudflat sample collected at Buan, Republic of Korea.43 Compound 58 strongly inhibited Salmonella enterica and B. subtilis with an MIC of 0.42 μg mL−1 for both strains. Compound 58 was less active against S. aureus and Proteus hauseri (MICs 6.2−12 μg mL−1). Noteworthy, it inhibited S. aureus sortase A, a transpeptidase enzyme involved in adhesion and host invasion by Gram-positive bacteria, more potently (IC50 value of 25 μg mL−1) than did the positive control, p-hydroxymercuribenzoic acid (pHMB) (IC50 35 μg mL−1). No antibacterial activity was detected with 59. 1220



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susceptible to 62 (MIC50 12 μg mL−1). The MIC50 for cell-wallcompromised E. coli D21f2tolC, a strain sensitive to hydrophobic agents such as salinamides, was 0.20 μg mL−1; Neisseria gonorrhoeae, Enterobacter cloacae, and S. aureus were not affected. Compounds 62−64 presented strong anti-RNA-polymerase (anti-RNAP) activity: the IC50 for S. aureus and for E. coli were 0.2−4 μM and 0.2−2 μM, respectively.46 By comparing the structures and RNAP-inhibitory activities of 62−64, the authors concluded that the epoxide in 63 and the chlorohydrin in 64 are not essential to the inhibitory bioactivity.

A known thiopeptide antibiotic, nosiheptide (65), was purified from Streptomyces sp. CNT-373 isolated from marine sediment collected on Nacula Island, Fiji.47 The peptide displayed strong activity against all contemporary MRSA strains resistant to linezolid, vancomycin, and daptomycin (MICs 0.03−0.25 μg mL−1), and the presence of 20% human serum did not hinder its anti-MRSA bioactivity. It also inhibited clinical isolates Enterococcus VRE-CUS and VRE-WMC, and M. catarrhalis ATCC25238 (MICs 0.12, 0.12, and 0.50 μg mL−1, respectively), as well as the contemporary hypervirulent BI/NAP1/O27 strain of Clostridium dif f icile (MIC 0.01 μg mL−1). E. coli and P. aeruginosa ATCC27853 were not inhibited (MIC > 4 μg mL−1). Compound 65 significantly (P < 0.03) protected against mortality in a murine intraperitoneal infection model with MRSA: 10 of 10 mice were still alive on the third day of infection, whereas 6/10 of the controls were dead on day 1. The authors conclude that because 65 is mass produced and used as an animal growth-promoting agent, it has an advantage over other antimicrobials that are still in early stage research. Family Micrococcaceae. Compound PM18110448 (later confirmed as kocurin49) (66) was produced by Kocuria sp. (Kocuria palustris44) obtained from a marine sponge collected at Palk Bay, India. Compound 66 was tested against 261 microorganisms and was found to inhibit standard and clinical isolates of S. aureus, both methicillin-sensitive and MRSA, with MICs ranging from 0.01 to 0.50 μg mL−1; clinical and laboratory strains of enterococci, both vancomycin-resistant (VRE) and vancomycin-sensitive (VSE) (MICs 0.01−16 μg mL−1);

Streptomyces sp. strain RL09-253-HVS-A, isolated from a marine sediment sample from Point Estero, CA, USA, produced known pyridyls, piericidin A1 (60) and the piericidin derivative mer-A 2026B (61).44 The paper discusses the previously uncharacterized activity of both compounds against the Gramnegative bacteria type III secretion system (T3SS), which is a virulence factor necessary for attacking host cells. T3SS inhibitors are a new class of antibiotics known as virulence blockers, which disarm pathogenic bacteria and prevent infection. At 30 μg mL−1, 60 and 61 reduced the secretion of the T3SS effector protein in Yersinia pseudotuberculosis by 65% and 45%, respectively. The authors suggest that blocking of T3SS does not occur by blocking bacterium−host cell interactions but instead occurs at an earlier stage of T3SS assembly. Collected in the Florida Keys, USA, from the surface of a jellyfish, Streptomyces sp. CNB-091 produced the new salinamide F (62) and the known salinamides A (63) and B (64).45 Both Gram-positive E. faecalis and Gram-negative H. inf luenzae were 1221



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derivatives pseudonocardians A (67), B (68), and C (69) and known deoxynyboquinone (70).51 Compounds 67, 68, and 70 inhibited S. aureus ATCC29213, E. faecalis ATCC 29212, and B. thuringiensis SCSIO BT01 with MIC values in the range of 1−4 μg mL−1. Structure−activity analysis revealed that the ethyl group at C-19, as in 68, is essential for its activity. Substitution of this ethyl group for a methyl moiety in 67 decreases the antibacterial activity by half. Glycosylation at C-10 in 69 prevented any inhibitory activity, similar to the inactivation exhibited by macrolide antibiotics as a consequence of bacterial resistance mechanisms. This is the first report on 70 obtained from a natural source.

S. epidermidis strains (MICs 0.01−1.0 μg mL−1); and several Bacillus species (0.01−0.02 μg mL−1). However, it was ineffective against 17 Gram-negative bacterial strains (data not shown). A dose of 5 mg kg−1 of 66 gave 100% protection in a murine septicemia model with MRSA strain E710 and showed comparable efficacy to that of the front-line antibiotics linezolid at 25 mg kg−1 and vancomycin at 150 mg kg−1 in a murine kidney infection model with VRE.

The Streptosporangium sp. strain DSZM 45942 isolated from a sediment sample collected at Trondheimsfjord, Norway, produced the known 1,6-dihydroxyphenazine-5,10-dioxide (iodinin) (71).52 The MICs of purified 71 for E. faecium CCUG 37832 and E. faecium CTC 492 were 0.70 and 0.35 μg mL−1, respectively. Under laboratory conditions, the isolate produced 0.6 g L−1 of 71, suggesting a high capacity to synthesize phenazines. The paper discusses the biosynthetic shikimate pathway leading from precursors erythrose 4-phosphate and phosphoenol pyruvate to 71. The authors suggest that, considering the wide spectrum of biological activity of 71, its hydrophobic nature and postexcretion adherence to the cell wall may provide an ecological advantage against competing microorganisms.

In another study49 on 66 purified from the same microbial species isolated from marine sponges from the Florida Keys, USA, MRSA was sensitive to the compound with MIC values in the submicromolar range (0.25 μg mL−1). Comparing the effect of 66 on wild-type and thiazomycin-resistant S. aureus strains indicated that both compounds have different modes of action. Thiazomycin, a similar thiazolyl peptide with a 29-membered cycle, binds to the elongation factor Tu (EF-Tu) and blocks its tRNA/amino acyl complex binding site, thus preventing peptide elongation by the ribosome.50 No activity of 66 was detected on Gram-negative bacteria at 16 μg mL−1. The structure of compound 66, synthesized by NRPS and PKS, was elucidated through spectroscopy and chemical methods and corrects that previously assigned to PM181104.43 Other Actinobacteria Genera. The actinomycete Pseudonocardia sp. was isolated from a deep-water sediment from the South China Sea and produced the new diazaanthraquinone

Table 2 summarizes the activities of the compounds discussed in this section, presenting MICs for several Gram-positive and Gram-negative bacteria.

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ANTIMICROBIAL METABOLITES FROM BACILLI The bioactive B. subtillis strain 109GGC020 was isolated from a marine sediment sample from Gageocho, Republic of Korea.53 The strain produced three new linear lipodi- and lipotetrapeptides named gageotetrins A−C (72−74). In broth dilution assays on S. aureus and B. subtillis, 72−74 displayed MICs ≤ 0.02 μg mL−1. Compounds 73 and 74 also displayed good activity on 1222



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Table 2. Minimum Inhibition Concentration (μg mL−1) of Metabolites from Actinobacteria compound

various MRSA strains/(VRSA)a

other S. aureus strains

B. subtilis

other bacteria

citreamicin θA (1) citreamicin θB (2) citreaglycon A (3) dehydrocitreaglycon A (4) fradimycin A (8) fradimycin B (9) compound MK844-mF10 (10) etamycin A (11) fijimycin A (12) fijimycin C (14) lobophorin G (21) lobophorin A (22) lobophorin B (23) lobophorin H (24) lobophorin F (26) actinomycin Xθβ (27) actinomycin X2 (28) actinomycin D (29) anthracimycin (33) 4-dehydro-4a-dechloronapyradiomycin A1 (34) 3-chloro-6,8-dihydroxy-8-α-lapachone (35) 3-dechloro-3-bromonapyradiomycin A1 (36) napyradiomycins A1 (37) 18-oxonapyradiomycin A1 (38) napyradiomycins B1 (39) napyradiomycins B3 (40) naphthomevalin (42) isoikarugamycin (47) 28-N-methylikarugamycin (48) macrolactin A1 (55) macrolactin B1 (56) lauramide diethanolamine (57) buanmycin (58) salinamide F (62) nosiheptide (65) kocurin (66) pseudonocardian A (67) pseudonocardian B (68) deoxynyboquinone (70)

0.25 0.25 8 >50c −d −d −d 1−16c 4−32c 8−32c −d −d −d −d −d −d −d −d 0.06−0.16 (0.12−0.25) −d −d −d −d −d −d −d −d 2−4 1−2 −d −d −d −d −d 0.03−0.12 (0.06−0.12) 0.01−2 −d −d −d

1 1 16c 16c 6 2 4 1−2 −d −d −d −d 100c 50c 5.2 −d −d −d 0.06−0.16 4 >128c 0.50 1 32c 1 0.50 1 −d −d 0.04 0.03 0.03 6.2 −d 0.06−0.12 0.01−2 4 2 1

0.25 0.25 8 8 −d −d −d −d −d −d 3.1 12c 1.6−3.1 1.6 6.2 −d −d −d −d 4 8 1 2 8 2 0.25 2 −d −d 0.02 0.03 0.02 0.42 −d −d −d −d −d −d

0.5b 0.5b 8b −d −d −d −d 1;e 8;f 16,c,g; 16h −d −d 1.6;i 32c,j 1.6;i 32c,j 0.8;i 16c,j −d −d 0.25;i 8j 0.25;i 1j 0.25;i 8j 0.03;k 0.25;f 0.12−0.25;g 4e −d −d −d −d −d −d −d −d −d −d 0.04;l 0.13m 0.03;l; 0.13m 0.03;l 0.02m 0.42;n 12h,o 0.20m;12h; 25c,p; 50c,q 0.01;r 0.12;g 0.50e 0.01−1g,s 2g 2g 1g

ref 25

27

28, 29 29 31 31, 32 32 33

36, 37 38

40 42

43 45 47 48, 49 51

a

MICs presented in brackets are for vancomycin-resistant S. aureus (VRSA). bStaphylococcus hemolyticus UST950701-004. cCompound inactive on some or all strains tested. dMIC values not available. eMoraxella catarrhalis ATCC 25238. fStreptococcus spp. gDrug-resistant Enterococcus spp.. hH. inf luenzae. iMycobacterium bovis BCG (Pasteur 1173P2). jMycobacterium tuberculosis H37Rv (ATCC27294). kBacillus anthracis. lP. aeruginosa. mE. coli. nSalmonella enterica. oProteus spp. pNeisseria gonorrhoeae. qEnterobacter cloacae. rClostridium dif f icile BI/NAP1/027. sStaphylococcus epidermidis.

Salmonella typhi (MICs 0.01 μg mL−1) and P. aeruginosa (MICs ≤ 0.03 μg mL−1). Compound 72 was less active on these Gramnegative bacteria (MICs 0.03 μg mL−1). This is the first report on the bioactivity of 72−74, which are uncommon linear lipopeptides that display a Leu-rich scaffold. The authors propose biosynthetic pathways based on NRPS for the production of gageotetrins. In a subsequent work, the authors54 reported production by the same strain of three new linear lipoheptapeptides, gageostatins A−C (75−77). When tested separately, compounds 75−77 inhibited both Gram-positive (S. aureus and B. subtillis; MICs 16−32 μg mL−1) and Gram-negative bacteria (S. typhi and P. aeruginosa; MICs 16−32 μg mL−1). However, a synergy between 75 and 76 resulted in lower MICs for S. aureus and P. aeruginosa (MIC 8 μg mL−1). These lipopeptides displayed the same amino acid sequence as those of the known

surfactins A−D with the difference that 75−77 are linear all-LLeu structures, opposed to surfactins A−D, which are L- and DLeu cyclic peptides. Additionally, there are new fatty acid moieties in 76 and 77. The marked difference in antibacterial activity between gageotetrins (72−74) and gageostatins (75− 77) may be explained by the number and composition in amino acid residues of the peptide chain. Both features influence the mode of action with which the chain attaches to the outer membrane of the pathogen, eventually leading to its death.55,56 A gorgonian from the South China Sea harbored Bacillus amyloliquefaciens SCSIO 00856, which produced a new 24membered-ring lactone, macrolactin V (78), and its known epimer macrolactin S (79).57 In a dilution method assay, S. aureus and E. coli were strongly inhibited by 78 (MICs 0.1 μg mL−1) and by 79 (MICs ≤ 0.3 μg mL−1). B. subtilis was highly sensitive to 78 (MIC 0.1 μg mL−1), but insensitive to 79 (MIC 100 μg mL−1). 1223



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inhibited B. subtilis and E. coli with MICs of 8 and 16 μg mL−1, respectively. Compounds 81−84 displayed low activity or were inactive (MICs ≥ 16 μg mL−1). Of note, the salinity of the culture medium influenced the production of the metabolites. Compounds 80−85 were detected at low (12 g L−1) but not at high salinity (32 g L−1). The antibacterial activities of the new macrolactins 80−82 were similar to those of published macrolactins, and no major structural differences existed among them. Comparison of the activity among the fatty acids showed that better inhibitory properties depended on unsaturation and the presence of hydroxy moieties (82−84) compared to saturated fatty acids.

Structure−activity analysis revealed that the antibacterial properties of compounds 78 and 79 depended on the configuration of the OH-7 of the epimer. Marine Bacillus sp. 09ID19458 produced three new 24membered macrolactones, macrolactins X−Z (80−82), two new hydroxy unsaturated fatty acids, linieodolides A (83) and B (84), and known macrolactinic acid (85). Compounds 85 and 80 1224



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Table 3. Minimum Inhibition Concentration (μg mL−1) of Metabolites from Bacilli

Cultivating the B. subtilis strain 109GGC020 in culture media containing different salinities (6.0, 18.5, 25.4, and 33.0 g L−1)59 and comparing 1H NMR data from their culture extracts suggested that a higher number of peaks corresponding to macrolactins can be obtained with salinity at 18.5 g L−1. This led to the isolation of three new macrolactin analogues, the gageomacrolactins 1−3 (86−88) and several known macrolactins. The microorganism was obtained from Gageo Reef sediment, Republic of Korea. Compound 86 was inhibitory toward Gram-positive bacteria (S. aureus, B. subtilis, and B. cereus) and Gram-negative bacteria (E. coli, S. typhi, and P. aeruginosa) with MICs in the range of 0.01−0.02 μg mL−1. Compounds 87 and 88 were less effective, with MICs varying from 0.02 to 0.10 μg mL−1. Other isolated macrolactins were not tested because their activities were already known. Comparing the structure− function of the new gageomacrolactins with those of known macrolactins illustrated that the antibacterial activity is not affected by the position of the epoxide moiety. However, the bioactivity is highly dependent on the free hydroxy at C-15 of the macrolactone ring. The presence of a methoxy or ketone decreased antibacterial activity.

compound gageotetrin A (72) gageotetrin B (73) gageotetrin C (74) gageostatin A (75) gageostatin B (76) gageostatin A+B (7576) macrolactin V (78) macrolactin S (79) macrolactin X (80) macrolactinic acid (85) gageomacrolactin 1 (86) gageomacrolactin 2 (87) gageomacrolactin 3 (88) protein BL-DZ1 (89) a

S. aureus

B. subtillis

E. coli

P. aeruginosa

S. typhi

0.01 0.03 0.03 16 16 8

0.01 0.01 0.03 16 32b 16

−a −a −a −a −a −a

0.03 0.03 0.01 16 16 8

0.03 0.01 0.01 16 32b 32b

53

0.10 0.10 −a −a

0.1 100b 16 8

0.1 0.3 16 8

−a −a −a −a

−a −a −a −a

57

0.01

0.01

0.02

0.01

0.02

59

0.06

0.06

0.02

0.03

0.02

0.06

0.06

0.06

0.03

0.03

−

−

−

3.1

−a

a

a

a

ref

54

58

60

b

MIC values not available. Compound inactive against the strain tested.

an efflux pump inhibitor, was evaluated in a mixture with several antibiotic classes (macrolide, tetracycline, fluoroquinolones, beta-lactam, aminoglycoside, and chloramphenicol) against three E. coli strains overexpressing efflux pumps. The association of 90 (2−128 μg mL−1) with the antibiotics caused a 2- to 16-fold decrease in their MICs. In addition, 90 displayed weak antibacterial effects on its own but with an MIC above 100 μg mL−1. Through the metabolomic mapping of the 36 Pseudoalteromonas isolates screened in the study, the presence of brominated metabolites was detected only within the P. piscicida phylogenetic clade, the most bioactive group, suggesting a relationship between halogenation and biosynthetic potential for antibiotic metabolites. The paper is the first report on 90 from a microbial source.

A protein obtained from Bacillus licheniformis D1 isolated from a marine mussel showed antibiofilm activity.60 A hypothetical protein (BL00275) from B. licheniformis ATCC 14580, derived from the National Center for Biotechnology Information (NCBI)61 database (accession number gi52082584), matched results from the matrix-assisted laser desorption ionization timeof-flight (MALDI-ToF) mass spectrometry analysis of the tryptic digest fingerprint of the isolated protein, which was designated BL-DZ1 (89). The MIC of purified 89 against P. aeruginosa and Bacillus pumilus was 3.1 μg mL−1, whereas the MICs for tetracycline and nalidixic acid were 40−80 and 1250−1500 μg mL−1, respectively. The 14 kDa protein also efficiently inhibited biofilm formation and broke up pre-established biofilms of P. aeruginosa and biofouling bacterium B. pumilus. Table 3 shows the antibacterial activities of the compounds discussed in this section against several microorganisms.

Complete genome sequencing of Pseudoalteromonas sp. SANK 7339063 revealed a new 97 kb plasmid, pTML1. Two essentially different gene clusters are embedded in the plasmid, and they synthesize distinct compounds, pseudomonic acid A (mupirocin) and pyrrothine, as well as the putative amide synthetase responsible for linking them together. A hybrid of two known antibiotics, the obtained mupirocin pyrrothine amide (91), resulted from the natural joining of two separate biosynthetic pathways. When fed mupirocin, pseudomonic acid defective mutants were able to synthesize the hybrid compound. Both 91 and its similar compound thiomarinol A (marinolic acid pyrrothine amide) (92) displayed antibacterial properties against MRSA (MIC ≤ 0.03 μg mL−1) and E. coli (MIC 0.5 μg mL−1). Mupirocin-resistant MRSA demanded higher MICs: 8 mg mL−1 with 92 and 16−32 mg mL−1 with the new compound. The authors noted that the pyrrothine addition enhances activity of pseudomonic acid A against tRNA synthase. The authors speculate that the ability to combine separate antibiotic pathways

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ANTIBACTERIAL METABOLITES FROM GAMMAPROTEOBACTERIA Marine Pseudoalteromonas piscicida produced the known 3,4dibromopyrrole-2,5-dione (90).62 The isolated bromopyrrole, 1225



Review

displayed by plasmid pTML1 sets a new chapter in the development of new derivatives of mupirocin that may be effective against MRSA.

The surface of a soft coral from the Red Sea at Aqaba, Jordan, provided Vibrio sp. WMBA,64 which produced seven new maleimide derivatives: aqabamycins A−D (93−96), a mixture of aqabamycins E (97) and E′ (98), and aqabamycins F (99) and G (100). In a serial dilution assay, compounds 97−99 displayed the highest activity against B. subtilis, Micrococcus luteus, E. coli, and Proteus vulgaris, with MICs between 3 and 25 μg mL−1. The MICs of compounds 93−96 and 100 for these bacteria varied between 25 and >100 μg mL−1. With the exception of 93, the aqabamycins contain a nitro moiety. Structure−activity studies on 93 and 95 revealed the necessity of the nitro substitution for increased antibacterial activity.

new molecules have been discovered with potent inhibitory activity against current MDR pathogens. Efforts should be put into the continuous exploration of the marine environment in the search for new bioactive compounds for the development of new drugs.

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■

CONCLUSION Marine bacteria have the ability to produce metabolites of varied chemical structures displaying antibacterial activities. These compounds present enormous potential for the discovery of new therapeutic leads in the development of drugs with which to fight the current antibiotic resistance threats. During 2010−2015, antibacterial compounds belonging to 28 diverse chemical classes were reported, of which 10 represented a new class of molecules. Over 30 new compounds were able to inhibit a variety of bacterial strains. Macrolactins A1 and B1 (55 and 56), gageotetrins A−C (72−74), and gageomacrolactins 1−3 (86− 88) display strong broad-spectrum activity against Gramnegative and Gram-positive bacteria. Compounds such as anthracimycin (33) and kocurin (66) present a highly selective antibacterial activity against Gram-positive bacteria, and their rescue ability in in vivo septicemia models points to possible therapeutic leads. Besides, the efficacy of 66 is comparable to that of frontline antibiotics. New mechanisms of action were also detected, although not completely elucidated, in 33, in which the antibacterial effect may be due to DNA and RNA synthesis disruption, and in 66, which seems to be different from that of its chemical analogue thiazomycin. Molecules belonging to a new class of antibacterial compounds, the virulence blockers, were also reported, such as piericidin A1 (60) and the piericidin derivative mer-A 2026B (61). With the increasing development of oceanographic science and metabolome screening techniques leading to the discovery of new species and metabolic profiles,

AUTHOR INFORMATION

Corresponding Author

*Phone: +55 19 35212167. Fax: +55 19 35212153. E-mail: [email protected]. ORCID

Claudia Schinke: 0000-0001-7890-1464 Thamires Martins: 0000-0002-3418-902X Sonia C. N. Queiroz: 0000-0002-1725-183X Itamar S. Melo: 0000-0003-2785-6725 Felix G. R. Reyes: 0000-0003-0126-3817 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully acknowledge the financial support received from the Brazilian Foundation for Improvement of Higher Education (CAPES) (Grants 1267382 and 1306489) and the National Council for Scientific and Technological Development (CNPq) (Grant 3053390/2013-9), Brazil.

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REFERENCES

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