Bioactive Secondary Metabolites from Bacillus subtilis - American

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Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX

Bioactive Secondary Metabolites from Bacillus subtilis: A Comprehensive Review Felix Kaspar,* Peter Neubauer, and Matthias Gimpel

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Institute of Biotechnology, Technical University of Berlin, Ackerstraße 76, 13355 Berlin, Germany ABSTRACT: Bacillus subtilis is widely underappreciated for its inherent biosynthetic potential. This report comprehensively summarizes the known bioactive secondary metabolites from B. subtilis and highlights potential applications as plant pathogen control agents, drugs, and biosurfactants. B. subtilis is well known for the production of cyclic lipopeptides exhibiting strong surfactant and antimicrobial activities, such as surfactins, iturins, and fengycins. Several polyketide-derived macrolides as well as nonribosomal peptides, dihydroisocoumarins, and linear lipopeptides with antimicrobial properties have been reported, demonstrating the biosynthetic arsenal of this bacterium. Promising efforts toward the application of B. subtilis strains and their natural products in areas of agriculture and medicine are underway. However, industrial-scale availability of these compounds is currently limited by low fermentation yields and challenging accessibility via synthesis, necessitating the development of genetically engineered strains and optimized cultivation processes. We hope that this review will attract renewed interest in this often-overlooked bacterium and its impressive biosynthetic skill set.

Bacillus subtilis is an ubiquitous Gram-positive bacterium that demonstrates unusual genetic adaptability, enabling it to colonize highly diverse habitats.1 Unlike several of the over 200 classified Bacillus species, B. subtilis is nonpathogenic and displays a great genetic diversity even among closely related strains.2,3 As a laboratory strain it has been the go-to model organism toward the understanding of fundamental principles of spore-forming Gram-positive bacteria for many decades.4 In the biotechnological industry it is a well-established workhorse employed for the synthesis of a broad product scope ranging from enzymes to fine chemicals.5,6 Its easy genetic manipulation due to natural competence, lack of outer membrane, and thoroughly characterized expression systems make it the organism of choice in many instances.5 Furthermore, it has gained traction as a biological control agent in agriculture by simultaneously fighting plant pathogens and promoting plant growth.7 Despite its application in the industrial bioproduction of cyclic lipopeptides, B. subtilis is, however, widely underappreciated for its inherent biosynthetic potential. Wild-type strains from various sources have demonstrated the impressive biosynthetic arsenal of this species. In fact, it has been estimated that 4−5% of a typical B. subtilis genome is dedicated solely to natural product biosynthesis.8 B. subtilis has long been recognized for the production of complex cyclic lipopeptides, including surfactins, iturins, and fengycins, which have attracted increased biotechnological and pharmaceutical interest as biosurfactants and antibiotics.9,10 In addition, several dihydroisocoumarins, polyketide-derived macrolides, and linear lipopeptides with potent antimicrobial properties © XXXX American Chemical Society and American Society of Pharmacognosy

have been reported more recently, shedding light on the biosynthetic capabilities of this bacterium. Here, we comprehensively summarize the known biologically active secondary metabolites from B. subtilis. While previous reviews have focused mainly on Bacillus lipopeptides9,10 or other bioactive metabolites including lipopeptides, lantibiotics, and macrolides,8,11 this review provides an update on recent discoveries in this field and presents the oftenneglected multitude of natural compounds from this bacterium. In the age of spreading antibiotic resistances and increasing demand for ecologically friendly approaches to pest control, it is easy to overlook common microorganisms such as B. subtilis and their natural products.7 Thus, we hope that this review will spark new interest in the application of B. subtilis in biological control systems and production of antibiotics and biosurfactants. This review is specifically limited to compounds isolated from strains identified as B. subtilis by 16S RNA and/or biochemical characterization and that have been shown to exhibit biological activity. Furthermore, we chose to include only compounds whose structure has been sufficiently characterized or that have been unambiguously identified and matched with literature data. For these reasons the diketopiperazines reported by Lu et al.12 and Elkahoui et al.13 or the lipoamicoumacins described by Li et al.,14 along with five derivatives of bioactive compounds,14−17 were not included in this review. Moreover, (lipo)peptides whose Received: February 5, 2019

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DOI: 10.1021/acs.jnatprod.9b00110 J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products

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Chart 1

Consequently, both laboratory and wild-type strains are regularly reported to produce at least one cyclic lipopeptide variant. In light of the extensive secondary literature about Bacillus cyclic lipopeptides, this chapter provides only a brief overview. Surfactin Family. Surfactin (1) is the only member of its family with known biological activity and also the most extensively studied lipopeptide from B. subtilis.38,39 Beyond its fibrinolytic activity, 1 exhibits remarkable surfactant activity and is considered one of the strongest known biosurfactants.40,41 Interestingly, several surfactin isomers with differing peptide backbones have been reported, revealing the flexibility of the responsible nonribosomal peptide synthase complex.10,20−22,31,40,42 So far, however, no data on the biological activity of the different isomers have been published. Surfactin’s (1) amphiphilic structure has led to its exploration across a broad range of applications, from antibiotic treatments relying on its membrane permeabilization properties10,43,44 and cancer therapy45 to enhanced oil recovery processes.40 Its biomedical applications and physicochemical properties have been reviewed previously.46,47 In particular, the inhibition of Salmonella enterica biofilms by 1 and its lytic effect against a range of viruses merit future investigation of its pharmacological value.48,49 Industrial-scale production of surfactin (1) might be feasible by high cell density fed-batch cultivation since excellent yields of more than 1 g L−1 have been reported for biotechnological processes employing wild-type Bacillus strains under optimized conditions.50,51 Strain and bioprocess engineering as well as promoter optimization have recently paved the road to surfactin (1) yields exceeding 10 g L−1.52−54 Conveniently, extraction and isolation of 1 from high-yielding culture broths is quickly and easily achieved via foam fractionation.50,55,56 Iturin Family. The iturin family comprises a class of lipoheptapeptides with antibacterial and antifungal activity. Their nomenclature differs from that of other lipopeptides in that compounds with the same peptide sequence, but different fatty acid chain, can have completely different names. For instance, iturin A (2), iturin AL (3), subtulene A (4), and mycosubtilin (5) all share the same peptide backbone (L-Asn,

amino acid configuration has not been conclusively established (e.g., fengycins C, D, and S, iturins D and E, and numerous surfactin variants, for many of which bioactivity is also unknown)18−23 were also omitted. Lantibiotics and other ribosomal peptides from B. subtilis are also not covered here, and the reader is referred to corresponding reviews.11,24,25 It should be noted that, for the sake of simplicity, all compounds in this article are shown as neutral molecules, which may not necessarily reflect their charge under standard conditions.

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CYCLIC LIPOPEPTIDES The most common and first natural products described from B. subtilis were cyclic lipopeptides.26−28 Their uncommon structure and potent bioactivity as well as surfactant activity made them attractive targets for isolation and structure elucidation. Their surfactant activity originates from their amphiphilic structure, created by a polar cyclic peptide backbone linked to a long branched or unbranched nonpolar alkyl chain. Generally, most of the cyclic lipopeptides from Bacillus are grouped into the surfactin, iturin, and fengycin families, according to their peptide scaffold. Surfactins and iturins carry a β-hydroxy or β-amino fatty acid in their ring structure, respectively, while fengycins are characterized by a terminal amide-linked β-hydroxy fatty acid. The alkyl residues include n-, iso-, and anteiso- chains of varying lengths, which leads to a multitude of possible isomers sharing the same peptide scaffold consisting of both L- and D-amino acids. Although these compounds have long been known, their biosynthetic pathways in B. subtilis have not been fully elucidated yet in all cases. It is generally agreed that their biosynthesis occurs via a nonribosomal pathway involving a multidomain enzyme complex that catalyzes amino acid linkage with the hydrophobic tail originating from the fatty acid biosynthesis pathway.29−37 The domain order, specificity, and organization vary between lipopeptides, as well as the amino acid composition. This in some cases requires amino acid racemization to ensure an ample supply of D-amino acids. Notably, cyclic lipopeptides are the most commonly observed secondary metabolites from B. subtilis, since their biosynthetic gene clusters are widespread among B. subtilis strains. B



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Chart 2

Fengycin Family. Fengycins A (10) and B (11) are fungicidal decapeptides that differ in one amino acid residue, with fengycin A (10) carrying a D-Ala and fengycin B (11) a DVal in their ring structure.79 Their rare octapeptide ring structure is created via macrolactonization between the TyrOH and the acyl moiety of the Ile. The lipid tail is formed by amide linkage of a β-hydroxy fatty acid with varying chain length and branching to the N-terminal amino acid.80,81 Recently, Li et al.82 reported a series of deoxyfengycin homologues characterized by ESI-MS/MS, revealing that the fatty acid β-OH group is not essential for the biological activity. Compared to other Bacillus antibiotics, fengycins are less toxic to plants, while exhibiting selective activity against pathogenic filamentous fungi such as Rhizoctonia solani and Paecilomyces varioti.79,81,83 Surprisingly, the bioactivity of the fengycins appears to mainly rely on the compound’s physiochemical properties rather than inhibiting a specific cellular target.84−86 Patel et al.85 have suggested an all-or-none mechanism of activity, relying on concentration-dependent membrane permeabilization that seems to be limited to filamentous fungi. Recent molecular dynamic simulations provide additional support for this hypothesized mode of action by demonstrating that the fungal cell wall might be more susceptible to lysis than the bacterial cell wall due to its specific lipid composition.87,88 This all-or-none mechanism might be additionally aided by the presence of further surfactants, including iturin A (2) or bacillomycins (7−9), which are often coproduced with 10 and 11, thus enabling an additive effect of different Bacillus lipopeptides.86 The closely related plipastatins were originally discovered independently from the fengycins in Bacillus cereus as inhibitors of phospholipase A2 before being detected in B. subtilis.89−92 The structures of plipastatins A1 (12), A2 (13), B1 (14), and B2 (15) are almost identical to their fengycin counterparts. The only difference arises from the inversion of the two Tyr stereocenters, lending the plipastatins a distinctively different tertiary structure of their peptide backbone. This structural

D-Tyr, D-Asn, L-Gln, L-Pro, D-Asn, L-Ser) while carrying different hydrophobic side chains. Like most lipopeptides, iturin A (2) is primarily membrane-active.57−59 It exerts its antimicrobial properties via insertion into the cytoplasmic membrane, forming pores by self-assembly.60−62 Owing to iturin A’s (2) potential to permeate the cell membrane, it has been suggested that there might be a more complex underlying mode of action involving further targets inside the cell.63 While its antibacterial properties are limited to certain Gram-positive bacteria including Micrococcus luteus, it possesses remarkable activity against a wide range of fungi at concentrations of 10 μg mL−1.64 In particular, its activity against phytopathogenic fungi has sparked interest into its application as a fungicide.64,65 For example, food preservation strategies relying on the fungicidal nature of 2 have been successfully investigated.66 Iturins B and C, which differ from 2 only by an exchange of a D-Asn with a DAsp, were found to be inactive against fungi.67 Iturin AL (3) carries a longer lipid chain than 2 and possesses comparable activity, by strongly inhibiting the growth of a range of fungi and yeasts.68 It is reasonable to assume that the antimicrobial activities of subtulene A (4) and mycosubtilin (5), which possess a virtually identical structure to 2, have a similar mode of action.27,69,70 Further members of the iturin family are the bacillomycins, which differ from the iturins by carrying a threonine instead of a serine in their ring structure. Overall, they exhibit surfactant activity similar to the iturins, but markedly decreased bioactivity. While bacillomycin D (6) has been found to strongly inhibit fungal growth and mediate biofilm formation in Bacillus amyloliquefaciens, bacillomycin F (7) has been shown to exert only weak antifungal and no antibacterial activity.28,71−75 Bacillomycins L (8) and Lc (9) show antifungal activity contributing to the antagonistic properties of B. subtilis against phytopathogenic fungi.26,71,76−78 Interestingly, the antifungal activity of the bacillomycins is strongly dependent on the chain length, supporting the idea that their mode of action is similar to that of the well-studied iturin A (2).76

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Phytophthora capsici with an IC50 of 1 μg mL−1, highlighting the potential of this B. subtilis strain as a biological control agent.95 To date, there are no data available concerning the biosynthesis or mode of action of these compounds, and as with other lipopeptides, isolation yields present a severe issue for further studies. Genetic manipulation of the producer strain might provide a feasible route to increase yields in this case, such as improved transformation methods for marine Bacillus spp. recently established by Liu et al.96,97 Generally, Bacillus cyclic lipopeptides are broadly applicable as plant pathogen control agents in agriculture9 and as valuable and eco-friendly biosurfactants.40 Due to their membrane permeation properties, they are considered intriguing antibiotic candidates for antifungal treatments with a small potential for resistance development.10,57 Their stability in aqueous solutions over a broad pH range further invites their application.26,79 Sufficient supply of these compounds might be accessible via bioproduction in their original strains in most cases, since the necessary biosynthetic gene clusters are widespread within the genus Bacillus and the identification of lipopeptide-overproducing strains is greatly aided by modern high-throughput screening methods. In fact, surfactins, iturins, and fengycins are already available commercially, although not yet in affordable rates. Future bioprocess development and genetic engineering are likely to lower the cost of these compounds significantly and thus encourage their use. However, momentarily, records of B. subtilis scale-up studies are scarce and often do not meet strict standards regarding product identification and characterization.

difference reinforces the large flexibility of the biosynthetic gene cluster that can occur through minor genetic aberrations.92 Notably, this seemingly small structural change results in a loss of fungicidal activity, despite the nonspecific all-ornone mechanism of action of the fengycins.89 Other Cyclic Lipopeptides. Locillomycins A−C (16−18) are antibacterial and antiviral nonapeptides isolated from the Chinese B. subtilis 916.93 Their biosynthetic gene cluster, which encodes four nonribosomal peptide synthetase genes, locA−locD, is unique among Bacillus species. Compounds 16− 18 differ in the length of their lipid tails (C13 to C15) and, contrary to other Bacillus lipopeptides, only contain one Damino acid. They are moderately active against methicillinresistant Staphylococcus aureus (MRSA) with minimal inhibitory concentrations (MIC) around 20 μg mL−1 and exhibit strong activity against the rice pathogen Xanthomonas oryzae, making the producer strain an attractive candidate for biological control of this bacterium.93 Commercial applications of the locillomycins (16−18) are, however, severely limited by low fermentation yields, necessitating further strain and/or bioprocess engineering. Bacilotetrins A (19) and B (20) are among the recently discovered compounds from the marine B. subtilis 109GGC020.94 They contain common elements of Bacillus lipopeptides, such as a β-hydroxy fatty acid tail, but their tetrapeptide backbone is unique among these lipopeptides. Notably, they exhibit moderate to weak activity against various MRSA strains, with MICs of 8−32 μg mL−1, while showing no toxicity against human cancer cell lines.94 The same strain also produced gageopeptins A (21) and B (22) under the same culture conditions. These heptapeptides possess moderate antifungal and antibacterial activity similar to the iturins (2−5) or fengycins (10, 11) with MICs of 4−8 μg mL−1 against R. solani, Colletotrichum acutatum, and Botrytis cinerea and MICs of 16 μg mL−1 against S. aureus and Pseudomonas aeruginosa, as determined by broth dilution assay. Gageopeptin A (22), in particular, strongly inhibits the motility of the phytopathogen

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LINEAR LIPOPEPTIDES So far, the only linear lipopeptides isolated from B. subtilis spp. are those from B. subtilis 109GGC020 reported by Tareq and co-workers.98−100 They share distinct structural characteristics in containing only L-amino acids, carrying (with one exception) an amide-linked anteiso-β-hydroxy fatty acid, and consist of only branched-chain (Leu, Val) and carboxylic acid D



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amino acids (Glu, Asp). While the C-3 configuration in the fatty acid has been established for all members of this family, the configurations of the methyl-bearing stereocenters have not been determined yet. Gageostatins A−C (23−25) are the longest representatives of this group, bearing seven amino acid residues.98 While gageostatin C (25) displays only weak antimicrobial activity, 23 and 24 exhibit strong antifungal properties, with MICs of 4−8 μg mL−1 against destructive fungal pathogens such as R. solani, C. acutatum, and B. cinerea. Interestingly, gageostatins A (23) and B (24) appear to act synergistically against fungi and Gram-positive and Gram-negative bacteria, as a mixture of the two compounds is markedly more active than the individual compounds. Future applications of the gageostatins (23−25) might, however, be critically limited by their broad cytotoxicity.98 Gageotetrins A−C (26−28) and gageopeptides A−D (29− 32) are di- and tetrapeptides with antimicrobial properties comparable to the gageostatins (23−25).99,100 In contrast to 23 and 24, they exhibit no cytotoxic activity, while strongly inhibiting a range of fungi and bacteria, including the blight and fruit rot pathogen P. capsici. Most likely, their biosyntheses occur via a shared pathway, with gageotetrin A (26) being a putative precursor to gageotetrin B (27) and other similar compounds differing only in their fatty acid chain. Notably, methyl substitution of the fatty acid chain and glutamic acid

esterification do not affect the biological activity significantly, whereas shortening of the peptide scaffold leads to a 2-fold increase of the MIC against fungi, as demonstrated by 26−28. These findings lend support to the theory that not only the fatty acid but also the peptide chain of the molecule are essential for biological activity.99 Together, the biological activity of the linear and cyclic lipopeptides produced by B. subtilis 109GGC020 present a strong rationale for the development of this strain toward applications as a biological control agent. While the isolation of these compounds presents a major challenge and may not be feasible due to their low individual yields, development of industrial-scale cultures for the production of the bacterium and its direct use to combat plant pathogens with its highly active and complex cocktail of lipopeptides may be a reasonable application.

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DIHYDROISOCOUMARINS The isocoumarins form a large and very diverse class of natural compounds with almost 200 known members.101 However, only a few dihydroisocoumarins have been reported from B. E



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been unraveled by Li and colleagues.17 They assigned a 47.4 kb region of B. subtilis 1779 with 16 open reading frames as the genes amiA-O and utilized a genomic capture and expression vector to express these in a heterologous host, thereby enabling it to produce amicoumacins A−C (33−35) as well as a nonbioactive analogue of 34 bearing an aromatic methoxy group. On the basis of their findings, they proposed an amicoumacin biosynthetic pathway via a hybrid modular polyketide synthase−nonribosomal peptide synthetase consisting of eight modules that synthesize two different preamicoumacins. The non-antibacterial preamicoumacins carry a lipid tail that is cleaved hydrolytically by the enzyme complex to liberate the active amicoumacins.17 Notably, the amicoumacins (33−36) display potent antibacterial and anti-inflammatory properties that make them attractive lead structures for drug development and thus sparked a number of total syntheses.109−113 Amicoumacin A (33) in particular has gained increased interest due to its strong inhibitory effect against S. aureus with a MIC below 1 μg mL−1 and its ability to induce cancer cell death via translation disruption.103,114 Its activity against MRSA has recently been shown to rely on inhibition of protein synthesis via stabilization of mRNA at the conserved E site of the ribosome and thus likely inhibits ribosome translocation during translation.115,116 Interestingly, the free C-8 hydroxy group of 33 and 34 appears to be vital for antiMRSA activity, as demonstrated by the near absence of activity of their phosphate esters.117 With amicoumacin A (33) being the most active member of this series and also a likely biosynthetic precursor to 34−36, the biological role of these derivatives remains unclear.102 Bacilosarcins A (37) and B (38) were isolated from B. subtilis TP-B0611 during a screening of marine-derived bacteria.118 Their unusual structures, including the unique 3oxa-6,9-diazabicyclo[3.3.1]nonane ring system of 37 as well as the rare 2-hydroxymorpholine moiety of 38, were confirmed by

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subtilis. Specifically, B. subtilis has been reported to produce isopropyl-8-hydroxy-3,4-dihydroisocoumarins carrying a highly functionalized amino acid or amide side chain. The first reported dihydroisocoumarins from Bacillus were amicoumacins A−C (33−35) and AI-77-F (36) isolated from Bacillus pumilus.102−107 Later they were also detected in B. subtilis during investigations of the antagonistic activity of B. subtilis 3 against the chronic gastritis pathogen Helicobacter pylori.108 The biosynthesis of these dihydroisocoumarins has recently Chart 7

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While the immediate value of the amicoumacins in agriculture or medicine may be limited, their anti-MRSA activity presents a viable starting point for natural-productinspired drug development. Their mode of action, however, is insufficiently characterized to date, necessitating further studies. While some dihydroisocoumarins discussed here have already been made available through synthesis, it remains to be demonstrated that these routes can be tailored toward cost-efficiency and sustainability. Nonetheless, total synthesis of amicoumacin analogues presents a powerful tool to investigate the structure−activity relationship of this scaffold.

total synthesis, shedding light on the structure−activity relationship of these compounds.113,119 Unlike the amicoumacins, 37 and 38 show only weak herbicidal properties, highlighting the importance of the side chain for biological activity. Additional support for this hypothesis is provided by the absence of activity in bacilosarcin C, which contains a carboxylic acid instead of an amide.14 Damxungmacin A (39) is an example of a bridged piperazine-containing dihydroisocoumarin. It possesses a rare heterocyclic ring system at its east end, lending it weak cytotoxic and antibacterial activity.16 Contrary to the other dihydroisocoumarins discussed above, the weak biological activity, complex structure, and low yield of 39 provide little rationale for additional bioprocess or synthesis development. The derivative damxungmacin B isolated along with 39 did not display biological activity at the tested concentrations. Despite being 8′-hydroxy-substituted, hetiamacin A (40, also known as PJS) displays excellent antibacterial activity.120,121 The strong activity against Gram-positive bacteria, including Streptococcus pneumoniae and oxacillin-resistant S. aureus and Staphylococcus epidermidis, with MICs of 0.5−2 μg mL−1 makes its structure−activity relationship an interesting area of investigation. Hetiamacin A’s (40) structure, featuring ring closure between the 8′-hydroxy group and the 10′-amine group, was recently elucidated by total synthesis, achieving the synthesis of 40 in two steps from amicoumacin B (34).121 This straightforward conversion might also provide a feasible approach to access hetiamacin A (40) semisynthetically from 33 or 34, given their inexpensive and easily scalable bioproduction.107 A similar ring-closed structure involving the 10′-amine group was also observed in hetiamacin B (41), which has been isolated from the same B. subtilis strain.15 Like the amicoumacins, 41 exhibits strong anti-MRSA activity. However, the absolute configuration of 41, as well as its unusual biosynthesis, remain unclear to date. Hetiamacins C and D from the same strains have not been investigated with respect to their bioactivity yet due to lack of isolated material.15 While the biosynthesis of the parent compounds amicoumacins A (33) and B (34) has been elucidated, similar studies on the other dihydroisocoumarins discussed here have not yet been reported. This may in part be due to the possibility that many of the amicoumacin analogues discussed here may be isolation artifacts. It has been shown that the bacilosarcins (37, 38) readily degrade to 33 and 34 under acidic conditions, so it would be reasonable to assume that 37 and 38 had been created by condensation of 33 or 34 with acetoin or similar metabolites during sample processing.118 Similarly, the hetiamacins (40, 41) could be formed via condensation of the parent scaffold 33 with formaldehyde or acetone. Likewise, the biosynthesis of 39 has not been explored yet; however, its structure suggests linkage of the N-terminus of 33 to a leucine, while the bridge might originate from nonenzymatic condensation with formaldehyde. Additionally, the presence of an N-oxide hints at oxidation during isolation. Taken together, these unusual structural features raise doubt over whether 39 is a natural product or rather an isolation artifact. Even though formation of these amicoumacin analogues as artifacts during isolation might be reasonable, their direct biosynthesis remains a possibility. Thus, the origin and biological role of these compounds remain elusive until further studies present conclusive evidence on this issue.

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OTHER PEPTIDES Bacilysin (42, also known as tetain) is among the oldest known natural products from B. subtilis, with the first reports from Gilliver122 and Newton123 dating back to 1949. However, the absolute structure of 42 had remained unclear until an enantioselective total synthesis was achieved over 40 years later.124−127 The dipeptide structure of bacilysin (42) consists of the noncanonical amino acid anticapsin linked to a L-Ala. Its considerable antibacterial activity has been proposed to arise from glucosamine synthase inhibition following hydrolysistriggered release of anticapsin.128,129 Furthermore, bacilysin (42) has been shown to inhibit a range of fungi, including Candida albicans, Saccharomyces cerevisiae, and the rice pathogen X. oryzae.128,130−132 Its selective disruptive effect on the cell wall of pathogenic fungi and algae species provides a rationale for the continued exploration of bacilysin-producing Bacillus strains as biocontrol agents.132,133 Chart 8

Chlorotetain (43) contains a rare chlorinated amino acid instead of the anticapsin moiety of bacilysin (42).127,134 In addition to its weak activity against bacteria, Rapp et al.134 reported the inhibition of several fungi by 43. Since chlorotetain (43) is only produced by very few Bacillus strains, its biosynthesis, as well as potential applications of its antibiotic activities, has not been investigated in depth yet. Nonetheless, its unusual chlorinated cyclohexenone scaffold has recently been rediscovered as a starting point for rational in silico drug design.135 Rhizocticins A−D (44−47) are antifungal di- and tripeptides consisting of the nonproteinogenic amino acid (Z)-L-2-amino-5-phosphono-3-pentenoic acid linked to an Arg with variable N-terminus.136,137 Their producer strain B. subtilis ATCC6633 carries a unique biosynthetic gene cluster encoding the enzyme machinery for the biosynthesis of phosphonates 44−47.138 Starting from phosphoenolpyruvate, the biosynthesis includes a rare aldol addition of oxaloacetate to phosphonoacetaldeyhde.138 The mode of action of the rhizocticins (44−47) relies on import into the fungal cell via the oligopeptide transport system and peptidolysis yielding free (Z)-L-2-amino-5-phosphono-3-pentenoic acid, which inhibits the threonine synthase.137,139 This intriguing mode of action G



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inhibition of class I phosphoinositide 3-kinases and subsequent signaling pathways. Additionally, Bae et al.156 reported the inhibition of human liver cytochrome P450 isoform CYP2C9. The molecular basis of the antiviral and antibacterial properties of 48 remains largely unexplored to date. Several 7-O derivatives of macrolactin A (48) have been reported. Typically, these are esters of short-chain carboxylic acids or glycosides. Similar to 48, 7-O-succinylmacrolactin A (49) exhibits mild antibacterial activity against S. aureus and cytotoxic activity.157−159 The antitumor activity of its TRIS salt has recently been evaluated in a mouse glioma model, revealing the significant antimigration and anti-invasion activity of 49.160 Like its parent compound, 49 exerts its antitumor activity through inhibition of PI3K and CYP2C9.155,156,161 Conveniently, 49 was shown to possess anti-inflammatory properties via the same pathway. 159,162 Compared to 48, 7-Osuccinylmacrolactin A (49) might present a superior clinical candidate as a prodrug due to its improved stability and comparable pharmacokinetics.163,164 7-O-Malonylmacrolactin A (50) possesses similar anti-inflammatory properties to 48 and 49, but has primarily gained attention for its anti-MRSA activity.158,159 Moreover, Bacillus strains producing 50 and bacillomycin D (6) have been applied as biological control agents against tropical bacterial and fungal pathogens in conjunction with organic fertilizers.165,166 Coproduction of multiple bioactive compounds might therefore present a fruitful strategy for broad-spectrum biological control, which emphasizes the value of Bacillus strains. Furthermore, unsaturated and aromatic macrolactins have been reported, with 7-O-6′-(2″-acetylphenyl)-5′-hydroxyhexanoate-macrolactin A (51) representing an example of esterification of two polyketide synthase products.167 Chakraborty et al.167 reported the isolation of 51 from a marine algaassociated B. subtilis and the extensive inhibitory properties of 51 against Gram-negative bacteria with MICs of 3−13 μg mL−1. However, the authors did not elucidate the relative or absolute structure of 51, leaving several stereocenters unassigned. In contrast, 7-O-2′E-butenoylmacrolactin A (52) was isolated from a deep sea sediment-derived B. subtilis and displays moderate antifungal activity against plant pathogens such as Pestalotiopsis theae and Colletotrichum gloeosporioides.168 The marine alga-associated B. subtilis MTCC 10403 yielded the moderately antibacterial 7-O-methyl-5′-hydroxy-3′-hepte-

encourages further investigations into the pharmacological properties of 44−47, although doubts about the antimicrobial activity of 44 have been raised by Gahungu et al.140 in their recent report of a total synthesis, necessitating validation of previous results. In addition to synthesis, large-scale availability of these compounds might be feasible via bioprocesses, as Borisova and colleagues138 have demonstrated that the rhizocticin biosynthetic machinery can be cloned into laboratory strains such as B. subtilis 168. Chart 9

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MACROLIDES Most of the bioactive macrolides from B. subtilis are biosynthetic derivatives of macrolactin A (48), a 24-membered polyketide-derived lactone with a multitude of intriguing biological activities.141,142 The macrolactins were originally isolated from an unidentified deep-sea bacterium, and the parent aglycon 48 immediately attracted the attention of chemists and pharmacologists due to its antibacterial, antiviral, and cytotoxic activity. It was found to inhibit S. aureus, Herpes simplex type I and II, murine tumor cells, and several fungi.141,143,144 Its simple structure featuring only four stereocenters and five double bonds granted easy access via synthesis, thus enabling a number of total syntheses constructing the macrolactone scaffold via key Wittig or aldol reactions.145−154 Despite its popularity as a synthetic target, surprisingly little is known about macrolactin A’s (48) modes of action. Kang and colleagues155 recently demonstrated that the antiangiogenic activity of 48 relies on Chart 10

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noate-macrolactin A (53).169 However, the authors did not report any further bioactivity data and only determined the antibacterial activity of 53 by agar diffusion. Furthermore, the absolute structure of 53 remains to be elucidated. Macrolactin B (54) was first isolated by Gustafson and colleagues in quantities too small to collect bioactivity data.141 It took more than 20 years for 54 to be reisolated from a marine B. subtilis and thoroughly characterized.144 Macrolactin B (54) is 7-O-β-glycosylated and exhibits significant broadspectrum antifungal activity. Unlike its aglycon 48, however, it is not cytotoxic, which may provide a possible insight into the structure−activity relationship of this class of natural products or hint at adverse cell penetration properties of 54 caused by the sugar moiety. Macrolactin W (55) is the only known example of a macrolactin that is both 7-O esterified and glycosylated. Its antibacterial and antifungal activities are similar to those of macrolactins A (48) and B (54), while possessing no cytotoxic activity.144,170 The cytotoxic, anti-inflammatory, and antiviral activities observed with the parent compound macrolactin A (48) have not been investigated for 51−55 so far. However, it is likely that these compounds are subject to hydrolysis in vivo, therefore liberating the active parent compound macrolactin A (48). 7,13-Epoxymacrolactin A (56) has been shown to inhibit mRNA expression of inducible nitric oxide synthase and interleukins IL-1β and IL-6.159 Its anti-inflammatory activity has been compared to that of 7-O-succinylmacrolactin A (49), although it is unlikely to occur via the same mode of action, considering the markedly lower activity of the parent compound 48 and derivatives 50 and 52.159 Antibacterial properties of 56 have not been reported. Macrolactin F (57) is closely related to macrolactin A (48). Compared to 48, the C-15 position is oxidized in 57 and it lacks the 16,17-double bond.141 Like macrolactin B (54), its bioactivity only became accessible upon reisolation, revealing its antifungal properties against pathogenic fungi such as R. solani and Candida albicans.144 Macrolactin N (58) was isolated following a screening for new bacterial peptide deformylase inhibitors.171 Its structure lacks the 13-hydroxy group of macrolactin F (57), and it exhibits weak antibacterial activity against S. aureus and Escherichia coli, with MICs of approximately 100 μg mL−1. However, it strongly inhibits S. aureus peptide deformylase and has been suggested to bind at the active site of the enzyme, indicating possible adverse cell penetration properties.171,172 Due to their very similar molecular structure and physicochemical properties, it would be reasonable to assume that other antibacterial macrolactins would exert their activity via the same pathway. Aside from the cyclic and linear lipopeptides 19−32, B. subtilis 109GGC020 has also yielded new antimicrobial gageomacrolactins 1−3 (59−61) under optimized cultivation conditions with respect to salinity.144 Structurally, they are closely related to the other macrolactins, with gageomacrolactin 1 (59) representing an epoxide of macrolactin A (48), gageomacrolactin 2 (60) an O-methylated macrolactin B (54), and gageomacrolactin 3 (61) a reduced macrolactin B (54). Their antibacterial and antifungal activities are comparable to those of the respective parent compounds, while they did not display any cytotoxicity. Thus, the cytotoxic activity of the macrolactins appears to be largely limited to the parent scaffold 48 and its succinyl derivative 49.

Chart 11

The confirmed lack of cytotoxicity of 54, 57, and 59−61 present valuable data points for future drug development based on this scaffold. However, therapeutic use of this class of compounds might be critically hindered by the broad spectrum of activity of macrolactin A (48) and its derivatives. Furthermore, additional insight into the mechanism of action of these compounds is required before considering clinical trials.173 While large-scale availability of 48 might be feasible via synthesis, other macrolactins have only been obtained through bioprocesses to date. Biotechnological production of these compounds may, however, not be practicable, given the challenging cultivation of marine bacteria in laboratory environments and meager yields of natural products from these sources (1−4 mg of pure compound from over 20 L of culture broth for some macrolactins).141,144 Even optimized fermentation processes with Bacillus amyloliquefaciens strains did not exceed a yield of 25 mg L−1 of 48.174,175 Cloning of the responsible biosynthesis clusters into more easy-to-handle laboratory strains necessitates the elucidation of all responsible genes and their in vitro assembly, which presents a considerable obstacle in the case of large enzyme complexes such as the polyketide synthesis machinery.176 Nonetheless, exploitation of the antibacterial and antifungal properties of the macrolactins in combination with lipopeptides in biological control systems remains an attractive application. Therefore, Bacillus strains producing both classes of compounds may be especially useful in agricultural settings where broad-spectrum pathogen control is required. Difficidin (62) and oxydifficidin (63) are antibacterial phosphorylated polyketide macrolides.177,178 While they had originally been isolated at Merck from a B. subtilis strain, most I



Review

well as self-protection from predatory fungi, shedding light on the natural chemical ecology of this genus.190,191

subsequent analyses concerning the biosynthesis of these compound were performed in B. amyloliquefaciens. Gene knockout studies and comparative genomics have revealed that 62 and 63, as well as the antibiotics bacillaene (64) and dihydrobacillaene (65), are produced via the polyketide synthase pathway.179−181 However, the elucidation of the biosynthetic pathways and genes involved has not proven straightforward; in-depth reviews on the state of the art are provided elsewhere.182,183 The difficidins (62, 63) are known to inhibit bacterial protein synthesis, lending them broadspectrum antibacterial activity against Gram-positive and Gram-negative bacteria. Salmonella typhimurium, MRSA, and streptomycin-resistant Morganella morganii are all inhibited by 62 and 63, with MICs of 2−32 μg mL−1.177 Their mode of action, as well as their absolute structures, are currently unknown. Notably, B. amyloliquefaciens strains commonly produce both difficidin (62) and bacilysin (42) and have therefore been studied intensively for the biological control of the rice pathogen X. oryzae and the cause of fire blight disease, Erwinia amylovora.132,184

Chart 13

Chart 12

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MISCELLANEOUS COMPOUNDS The antibacterial fused-ring polyketide aurantinin B (66) was originally isolated from Bacillus aurantinus.192 Together with two new analogues, aurantinins C (67) and D (68), it was recently reisolated following a genome-mining approach for novel polyketides in B. subtilis Fmb60.193 Their quite unusual structures feature five-, six-, seven-, and eight-membered rings, as well as a highly substituted tail most likely synthesized by a modular trans-acyltransferase polyketide synthase.193 However, so far the absolute structures of 66−68 have not been elucidated, leaving several questions regarding configurations unanswered. Aurantinins B−D (66−68) possess strong antibacterial activity against Gram-positive bacteria, including M. luteus, B. pumilus, and MRSA with MICs below 7 μg mL−1. Their mode of action appears to rely on cell wall and membrane disruption, causing leakage of cytoplasm and cell death.193 Furthermore, the lack of cytotoxicity and activity against Gram-negative bacteria points to a highly selective mode of action, potentially allowing a broad spectrum of applications of 66−68.192,193 However, possible applications of the aurantinins (66−68) or their producer strain have not been investigated to date.

Similar to difficidin (62), bacillaene (64) and dihydrobacillaene (65) disrupt protein synthesis in prokaryotes via an unknown mechanism.185 To date, little is known about the spectrum of activity of 64 and 65, beyond the initial agar plate diffusion assays by Patel and co-workers, that established the moderate activity of these compounds against various Grampositive and Gram-negative bacteria.185 The linear structures of 64 and 65 feature two amide bonds and a highly unstable conjugated hexaene or pentaene system, respectively.186 However, the absolute structures of 64 and 65 are still unclear, as the configurations of one methyl- and two hydroxybearing stereocenters remain to be determined. Their biosynthesis occurs via a rare polyketide−nonribosomal peptide synthetase pathway, involving scaffold assembly, as well as unusual β,γ-dehydration and branch introduction, by a transacyltransferase polyketide synthase.186−188 However, direct applications of difficidins (62, 63) and bacillaenes (64, 65) might be severely restricted due to their extreme instability at higher temperatures and their sensitivity to oxygen and light.178,186 Nonetheless, bacillaene production by Bacillus strains might prove advantageous in biological control settings, since its onset occurs typically much earlier than lipopeptide biosynthesis in the B. subtilis life cycle.189 Interestingly, bacillaene production has also been linked to putative symbiotic relationships between Bacillus sp. and termites as

Chart 14

J



Review

The rare occurrence and the weak to moderate bioactivity of 66−76 promise little potential for applications. Therefore, further investigations into synthetic routes toward these compounds and improvements in bioprocesses are unlikely. Nevertheless, they provide intriguing insights into the biosynthetic capabilities of B. subtilis.

So far, only few secondary metabolites have been reported from B. subtilis that do not originate from a polyketide or nonribosomal peptide synthetase pathway. The phospholipid antibiotic bacilysocin (69) presents a unique example of a modified phospholipid from B. subtilis.194 The structure of 69 features a central glycerol terminally linked to an anteiso-fatty acid tail and a glyceryl phosphate. The proposed biosynthesis of 69 starting from abundant phosphatidic acid includes conversion to phosphatidylglycerol before ester hydrolysis yields the free center hydroxy group.194 Bacilysocin (69) is weakly active against Gram-positive bacteria such as S. aureus and fungi, including Candida pseudotropicalis and S. cerevisiae.194 The biological role of 69 remains unclear to date, since the mode of action, as well as the intraspecific activity of this compound have not been elucidated yet.

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CONCLUDING REMARKS Common microorganisms such as B. subtilis are regularly overlooked and underestimated for their biosynthetic abilities; nonetheless they deserve our recognition. Here, we have comprehensively reviewed the known bioactive secondary metabolites from B. subtilis and critically discussed applications and issues of limited availability. B. subtilis produces a range of fungicidal lipopeptides such as surfactins, iturins, and fengycins, which could be valuable tools in many areas of agriculture and medicine. Furthermore, several dihydroisocoumarins with anti-MRSA activity and macrolides with cytotoxic properties are known and are currently further investigated, including applications in clinical settings. However, it should be noted that there is a great difference between the biosynthetic capabilities of different B. subtilis strains, since many of the compounds discussed here have been reported from only one strain, whereas others are known from various sources (Table 1). This intraspecific diversity of secondary metabolite production is most likely related to horizontal gene transfer enabled by the natural competence of B. subtilis under stress.211,212 Given the diversity of habitats that B. subtilis has conquered, it is not surprising that some strains have acquired new biosynthetic gene clusters by combining their own and external DNA.1,2 In fact, one might even argue that the diversity of natural products from B. subtilis is rather limited compared to the Streptomycetes and various fungi that grow in the same habitat.213,214 Nevertheless, considering the wealth of biosynthetic potential harbored by soil microorganisms, we speculate that we are yet to uncover the entire extent of the natural product repertoire of B. subtilis. Overall, their biosynthetic skill set makes B. subtilis strains increasingly promising candidates for environmentally friendly plant pathogen control and development of anti-infectives, cancer treatment drugs, and biosurfactants. As a biological control strain, in particular, B. subtilis unfolds its full potential by coproducing various bioactive compounds such as lipopeptides and polyketides, thus ensuring broad-spectrum pathogen control. However, appropriate exploitation of other B. subtilis metabolites such as amicoumacins and macrolactins is currently hampered by insufficient understanding of the

Chart 15

The aminosaccharide 3,3′-neotrehalosadiamine (70) isolated from the RNA polymerase-mutated B. subtilis 84R5 displayed moderate activity against S. aureus and Klebsiella pneumoniae as determined by an agar diffusion assay.195,196 A putative aminotransferase from B. subtilis required for the biosynthesis of 70 has been isolated and characterized by crystallization.197 Beyond that, however, the biosynthetic pathway of 70 has not been thoroughly investigated and the mode of action is still unclear. Recently, Chakraborty and colleagues reported the isolation of four new antibacterial furanoids (71−74) and two new antibacterial pyranoids (75 and 76) from a marine-algaassociated B. subtilis.198,199 Their biosynthesis has been speculated to occur via hitherto unverified polyketide synthase-like pathways. Compounds 71−76 were found to be moderately active against Gram-negative pathogens such as Vibrio parahaemolyticus.198 Their absolute structures, antifungal activity, and their cytotoxicity and activity against Grampositive bacteria, however, were not reported. Chart 16

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Review

Table 1. Bioactive Secondary Metabolites from B. subtilis and Their Producer Strains compound Cyclic Lipopeptides surfactin (1) iturin A (2) iturin AL (3) subtulene A (4) mycosubtilin (5) bacillomycin D (6) bacillomycin F (7) bacillomycin L (8) bacillomycin Lc (9) fengycins (10, 11) plipastatins (12-15) locillomycins (16−18) bacilotetrins (19, 20) gageopeptins (21, 22) Linear Lipopeptides gageostatins (23−25) gageotetrins (26−28) gageopeptides (29−32) Dihydroisocoumarins amicoumacins A-C (33−35) AI-77-F (36) bacilosarcins (37, 38) damxungmacin A (39) hetiamacin A and B (40, 41) Other Peptides bacilysin (42) chlorotetain (43) Rhizocticins (44-47)

B. subtilis producer strain

origin Vc V Germany Thailand

B. subtilis A114 B. subtilis SSE3

V V France V USA V V

B. subtilis I164 B. subtilis FS94-14

B. subtilis 916 B. subtilis 109GGC020 B. subtilis 109GGC020 B. subtilis 109GGC020 B. subtilis 109GGC020 B. subtilis 109GGC020

B. B. B. B.

subtilis subtilis subtilis subtilis

B1779 TP-B0611 XZ-7 PJS

B. subtilis BGSC 1E2 B. subtilis ATCC 6633

Macrolides macrolactin A (48) 7-O-succinyl-macrolactin A (49) 7-O-malonyl-macrolactin A (50) 7-O-6′(2″-acetylphenyl)-5′-hydroxyhexanoatemacrolactin A (51) 7-O-2′E-butenoyl-macrolactin A (52) 7-O-methyl-5′-hydroxy-3′-heptenoate-macrolactin A (53) macrolactin B (54) macrolactin W (55) 7,13-epoxyl-macrolactin A (56) macrolactin F (57) macrolactin N (58) gageomacrolactins (59−61) difficidins (62, 63) bacillaenes (64, 65) Miscellaneous Compounds aurantinins B-D (66−68) bacilysocin (69)

B. subtilis MTCC 10403 B. subtilis B5 B. subtilis MTCC 10403 B. subtilis 109GGC020 B. subtilis 109GGC020 B. subtilis B5 B. subtilis 109GGC020 B. subtilis AT29 B. subtilis 109GGC020

B. subtilis fmb60 B. subtilis 168

L

habitat

freshwater lake shrimp shell waste

main bioactivitya

ref

broad spectrumb antifungal antifungal antifungal

38, 56, 200 58, 200 68 69 27, 58, 73 67, 76, 79, 89,

China Korea

paddy soil marine sediment

antifungal antifungal antifungal antifungal antifungal antifungal inhibition of phospholipase A2 antibacterial antibacterial

Korea

marine sediment

antifungal

95

Korea

marine sediment

antifungal

98

Korea

marine sediment

antifungal

99

Korea

marine sediment

antifungal

100

V Red sea Japan China China

NR fish intestine soil plant leaf

antibacterial antibacterial herbicidal cytotoxic antibacterial

108 14 118 16 15, 120

V NR unknown

NR soil

antifungal antibacterial antifungal

83 134 136

V

cytotoxic

V V India

marine algae

cytotoxic antibacterial antibacterial

144, 157, 158, 168 157, 158, 168 158, 168 167

China India

marine algae marine algae

antifungal antibacterial

168 199

Korea

marine algae

antifungal

144

Korea

marine algae

antibacterial

144

China

marine sediment

159

Korea

marine algae

inhibition of mRNA expression antifungal

144

Korea Korea

soil marine algae

antibacterial antibacterial

171 144

V V


178, 210 185, 186, 190

China compost X-ray mutant of B. subtilis Marburg


193 194

NRd tree xylem

201 202, 203 204 205 206, 207 208, 209

93 94



Review

Table 1. continued compound Miscellaneous Compounds 3,3′-neo-trehalosadiamine (70) furanoids 71−74 pyranoids 75 and 76

B. subtilis producer strain

origin

B. subtilis 84R5 B. subtilis MTCC 10403 B. subtilis MTCC 10407

habitat

main bioactivitya

ref

transformation mutant of B. subtilis 61884 India marine algae

antibacterial

196

antibacterial

198

India

antibacterial

199

marine algae

a,b

Please see main text for other bioactivities as well as bioassay data. cVarious (selected examples are given in the references). dNot reported; nonB. subtilis producer strains and heterologous B. subtilis producer strains were not included. (13) Elkahoui, S.; Abdel rahim, H.; Tabbene, O.; Shaaban, M.; Limam, F.; Laatsch, H. Nat. Prod. Res. 2013, 27, 108−116. (14) Li, Y.; Xu, Y.; Liu, L.; Han, Z.; Lai, P. Y.; Guo, X.; Zhang, X.; Lin, W.; Qian, P.-Y. Mar. Drugs 2012, 10, 319−328. (15) Liu, S.; Han, X.; Jiang, Z.; Wu, G.; Hu, X.; You, X.; Jiang, J.; Zhang, Y.; Sun, C. J. Antibiot. 2016, 69, 769. (16) Tang, H.-L.; Sun, C.-H.; Hu, X.-X.; You, X.-F.; Wang, M.; Liu, S.-W. Molecules 2016, 21, 1601. (17) Li, Y.; Li, Z.; Yamanaka, K.; Xu, Y.; Zhang, W.; Vlamakis, H.; Kolter, R.; Moore, B. S.; Qian, P.-Y. Sci. Rep. 2015, 5, 9383. (18) Li, X.-Y.; Mao, Z.-C.; Wang, Y.-H.; Wu, Y.-X.; He, Y.-Q.; Long, C.-L. J. Mol. Microbiol. Biotechnol. 2012, 22, 83−93. (19) Besson, F.; Michel, G. J. Antibiot. 1987, 40, 437−442. (20) Peypoux, F.; Bonmatin, J.-M.; Labbé, H.; Das, B. C.; Ptak, M.; Michel, G. Eur. J. Biochem. 1991, 202, 101−106. (21) Peypoux, F.; Bonmatin, J. M.; Labbe, H.; Grangemard, I.; Das, B. C.; Ptak, M.; Wallach, J.; Michel, G. Eur. J. Biochem. 1994, 224, 89−96. (22) Grangemard, I.; Peypoux, F.; Wallach, J.; Das, B. C.; Labbé, H.; Caille, A.; Genest, M.; Maget-Dana, R.; Ptak, M.; Bonmatin, J.-M. J. Pept. Sci. 1997, 3, 145−154. (23) Kowall, M.; Vater, J.; Kluge, B.; Stein, T.; Franke, P.; Ziessow, D. J. Colloid Interface Sci. 1998, 204, 1−8. (24) Barbosa, J.; Caetano, T.; Mendo, S. J. Nat. Prod. 2015, 78, 2850−2866. (25) Lee, H.; Kim, H.-Y. J. Microbiol. Biotechnol. 2011, 21, 229−235. (26) Landy, M.; Warren, G. H.; Rosenman, M. Exp. Biol. Med. 1948, 67, 539−541. (27) Walton, R. B.; Woodruff, H. B. J. Clin. Invest. 1949, 28, 924− 926. (28) Raubitschek, F.; Dostrovsky, A. Dermatology 1950, 100, 45−49. (29) Besson, F.; Michel, G. Biotechnol. Lett. 1992, 14, 1013−1018. (30) Kluge, B.; Vater, J.; Salnikow, J.; Eckart, K. FEBS Lett. 1988, 231, 107−110. (31) Luo, C.; Liu, X.; Zhou, H.; Wang, X.; Chen, Z. Appl. Environ. Microbiol. 2015, 81, 422−431. (32) Moyne, A.-L.; Cleveland, T. E.; Tuzun, S. FEMS Microbiol. Lett. 2004, 234, 43−49. (33) Desai, J. D.; Banat, I. M. Microbiol. Mol. Biol. Rev. 1997, 61, 47. (34) Steller, S.; Vollenbroich, D.; Leenders, F.; Stein, T.; Conrad, B.; Hofemeister, J.; Jacques, P.; Thonart, P.; Vater, J. Chem. Biol. 1999, 6, 31−41. (35) Besson, F.; Hourdou, M.-L.; Michel, G. Biochim. Biophys. Acta, Gen. Subj. 1990, 1036, 101−106. (36) Finking, R.; Marahiel, M. A. Annu. Rev. Microbiol. 2004, 58, 453−488. (37) Samel, S. A.; Wagner, B.; Marahiel, M. A.; Essen, L.-O. J. Mol. Biol. 2006, 359, 876−889. (38) Arima, K.; Kakinuma, A.; Tamura, G. Biochem. Biophys. Res. Commun. 1968, 31, 488−494. (39) Kakinuma, A.; Sugino, H.; Isono, M.; Tamura, G.; Arima, K. Agric. Biol. Chem. 1969, 33, 973−976. (40) Liu, J.-F.; Mbadinga, S. M.; Yang, S.-Z.; Gu, J.-D.; Mu, B.-Z. Int. J. Mol. Sci. 2015, 16, 4814−4837.

modes of action and limited access to larger quantities. In order to overcome these challenges, further studies toward the elucidation of the molecular targets of these compounds as well as the development and optimization of suitable bioprocesses for their cost-efficient production are of crucial importance. Thus, we hope that this article will attract renewed interest in this often-neglected bacterium and the application of its respectable biosynthetic arsenal. Finally, we encourage the scientific community not to overlook and discredit common and ubiquitous microorganisms, as they may exhibit an unexpected diversity of natural products, as demonstrated by this review for B. subtilis.

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AUTHOR INFORMATION

Corresponding Author

*E-mail (F. Kaspar): [email protected]. Tel: +49 (0)178 314 9337. ORCID

Felix Kaspar: 0000-0001-6391-043X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Dr. R. J. Capon and M. R. L. Stone for valuable suggestions on previous drafts of the manuscript. This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy − EXC 2008/1 (UniSysCat) − 390540038

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