TY - JOUR
AU - Kolodkin-Gal,, Ilana
AB - ABSTRACT A sustainable future increasing depends on our capacity to utilize beneficial plant microbiomes to meet our growing needs. Plant microbiome symbiosis is a hallmark of the beneficial interactions between bacteria and their host. Specifically, colonization of plant roots by biocontrol agents and plant growth-promoting bacteria can play an important role in maintaining the optimal rhizosphere environment, supporting plant growth and promoting its fitness. Rhizosphere communities confer immunity against a wide range of foliar diseases by secreting antibiotics and activating plant defences. At the same time, the rhizosphere is a highly competitive niche, with multiple microbial species competing for space and resources, engaged in an arms race involving the production of a vast array of antibiotics and utilization of a variety of antibiotic resistance mechanisms. Therefore, elucidating the mechanisms that govern antibiotic production and resistance in the rhizosphere is of great significance for designing beneficial communities with enhanced biocontrol properties. In this review, we used Bacillus subtilis and B. amyloliquefaciens as models to investigate the genetics of antibiosis and the potential for its translation of into improved plant microbiome performance. bacillus, rhizosphere, antibiotics, surfactin, biocontrol, microbiome BACILLUS SPECIES IN THE RHIZOSPHERE In the rhizosphere, bacteria establish complex and structured communities, often called biofilms. In a biofilm, microbial cells are held together by organic and inorganic extracellular matrices (Branda et al. 2005; Keren-Paz and Kolodkin-Gal 2019). Microbial cells use a variety of mechanisms to coordinate activity within these communities, both within and across species (Parsek and Greenberg 2005; Elias and Banin 2012). In many instances, biofilms provide benefits to other organisms. For example, biocontrol agents form biofilms on the surface of plant roots, thereby preventing the growth of pathogenic bacteria and fungi (Rudrappa et al. 2010; Beys-da-Silva et al. 2014). Bacterial biofilms also play an active role in the bioremediation of contaminated soils (Jian-Zhou et al. 2015) and in carbon dioxide sequestration (Lidbury et al. 2012). Thus, developing an experimental framework for the study of biofilm communities will provide the foundation for technological (Nevin et al. 2010; Torres et al. 2010), agricultural (Chen et al. 2013; Huws et al. 2018) and ecological (Sanchez 2011; Cha et al. 2012) advances. Rhizobacteria can promote plant growth directly by colonization of the root and exert beneficial effects on plant growth and development (Kloepper, Ryu and Zhang 2004). These bacteria are often designated plant growth-promoting rhizobacteria (PGPR). To date, various PGPR have been isolated, including various other Bacillus species, Burkholderia cepacia and Pseudomonas fluorescens. Similar to the activities of beneficial gut microbiota, beneficial rhizobacteria can also confer fitness on their hosts by activating their immune system, and antibiosis of pathogens (Berg et al. 2017; Berg and Raaijmakers 2018; Allaband et al. 2019). In addition to the direct promotion of plant growth, PGPR enhance the efficiency of fertilizers and aid in degrading xenobiotic compounds. Overall, the capacities of beneficial rhizobacteria as PGPR and biocontrol agents can be utilized to reduce and/or replace hazardous pesticides and fertilizers in agriculture, with significantly less damage to the natural diversity and function of the native microbiome (Adam et al. 2016; Berg et al. 2017). Bacillus subtilis and its related species, such as B. amyloliquefaciens, B. velezensis and B. mojavensis, represent an intriguing model of biocontrol agents and PGPR, which is of great relevance to ecology and agriculture (Fan et al. 2017a). In ecological and agricultural settings, these bacterial species are highly efficient biocontrol agents, protecting plants from both fungal and bacterial pathogens (Emmert and Handelsman 1999; Ongena and Jacques 2008). This protection is proposed to be mediated, in part, by the formation of biofilms (Raaijmakers et al. 2010; Rudrappa et al. 2010), and also by the production of a wide range of antibiotics (Nagorska, Bikowski and Obuchowski 2007). Furthermore, B. subtilis elicits induced systemic resistance (ISR) throughout the entire plant via a secondary metabolite-mediated mechanism. The resistance induced constitutes a simultaneous increase in the level of basal resistance to several pathogens under conditions in which the inducing bacteria and the challenging pathogen remain spatially separated. This situation is beneficial under natural conditions with the existence of multiple pathogens. Volatile organic compounds produced by B. subtilis were found to be primary determinants of both plant growth promotion and elicitation of ISR (Kloepper, Ryu and Zhang 2004; Kumar et al. 2012; Ogran et al. 2019). The successful colonization of plant roots (the rhizoplane) depends on the capacity of B. subtilis to form biofilms and occurs at preferred sites of root exudation, where plants release C- and N-containing compounds into the surrounding soil (Bais, Fall and Vivanco 2004). These beneficial effects of B. subtilis and related species also depend on their ability to form endospores, which allow the persistence of the bacteria in the soil. B. subtilis, B. amyloliquefaciens, B. velezensis and B. mojavensis, have been adopted primarily for biological control of bacterial, viral and fungal soil-borne plant pathogens and as plant growth promoting agents (Kloepper, Ryu and Zhang 2004; Nagorska, Bikowski and Obuchowski 2007). A growing food insecurity (Carvalho 2006) has generated an expanding dependence for biocontrol agents and biofertilizers. These biological solutions can reduce the requirement for hazardous (cancerous, teratogenic and toxic) chemical fertilizers and pesticides (Mahanty et al. 2017; Backer et al. 2018). Therefore, in this review, we provide a comprehensive summary of the biocontrol properties of the B. subtilis clade, and their applications. Various examples demonstrate the potency of this bacterium and related species in plant protection. B. subtilis was shown to protect plants against infections caused by Ralstonia solanacearum, which causes wilt disease in a wide host range (Chen et al. 2013), as well as providing protection against the whitefly Bemisia tabaci (Valenzuela-Soto et al. 2010), and the cucumber mosaic virus or Pseudomonas syringae (Ryu et al. 2007). The plant growth promoting and biocontrol capacities of B. subtilis and related species are based on the competitive suppression of soil-borne pathogens by the local production of siderophores or broad-spectrum antibiotics. It is now appreciated that Bacillus clade is a competent antibiotic producer (Sansinenea and Ortiz 2011). Approximately 5% of the B. subtilis genome is dedicated to the synthesis of antimicrobial molecules by non-ribosomal peptide synthetases (NRPS) or polyketide synthases (PKS/NRPS), including several classes of polyketides and bacteriocins (Stein 2005; Ongena and Jacques 2008; Kinsella et al. 2009). Surfactin in particular, which is a cyclic lipopeptide with surface and membrane activity was shown to contribute to the biocontrol capacity of B. subtilis (Bais, Fall and Vivanco 2004; Gao et al. 2013) (Manifested in symbolic Fig. 1A). Moreover, B. subtilis secondary metabolites activate ISR throughout the entire plant (Marten, Smalla and Berg 2000; Ryu et al. 2003; Kloepper, Ryu and Zhang 2004; Kumar et al. 2012). One key issue in studying the rhizosphere competence is obtaining a direct evidence of the necessity for genes responsible for antibiotic production, which is only feasible in genetically manipulatable organisms. Figure 1. Open in new tabDownload slide The rhizosphere as a niche governed by antibiotic production. (A) A schematic figurative diagram of the habitat in which the different illustrated antibiotics exert their activities. In the enlargement, antibiotics are represented to reflect their distinctive sizes. (B) A flow chart of potential translation of characterization of APGs and ARGs to the field. Pale blue- experiments to be performed in the lab. Green-experiments to be performed in the field. Red-generation of GMOs for agriculture.. Figure 1. Open in new tabDownload slide The rhizosphere as a niche governed by antibiotic production. (A) A schematic figurative diagram of the habitat in which the different illustrated antibiotics exert their activities. In the enlargement, antibiotics are represented to reflect their distinctive sizes. (B) A flow chart of potential translation of characterization of APGs and ARGs to the field. Pale blue- experiments to be performed in the lab. Green-experiments to be performed in the field. Red-generation of GMOs for agriculture.. Within the rhizosphere, soil-borne microorganisms, including multiple species of bacteria, compete for organic material and bacteria often cluster with their own species to form micro-biofilms (Berg and Smalla 2009). As the rhizosphere is a highly competitive niche, with multiple microbial species competing for space and resources, rhizosphere residents, including Bacilli, engage in an arms race involving the production of a vast array of antibiotics and utilization of a variety of antibiotic resistance mechanisms. Therefore, the competitiveness of B. subtilis and related species in the rhizosphere depends not only on antibiotic production, but also on antibiotic resistance. Antibiotic Resistance Genes (ARGs) are rarely examined for their contribution to rhizosphere competence in undisturbed soils, and the B. subtilis clade serves as a highly compatible model to assess their functions. Genetic tools and fundamental research can promote our understanding of antibiosis and complex multi-species interactions in natural habitats. To infer causal relationships between microbiota membership and host phenotypes and to facilitate the rational design of novel protective communities requires the translation of basic research from the laboratory into successful biocontrol within the complex habitat of the rhizosphere. Here, we use the B. subtilis clade as a model to demonstrate the feasibility of a workflow from the lab into the field. Notably, B, subtilis strains lost rhizocompetence and biocontrol properties during domestication (McLoon et al. 2011; Chen et al. 2013), which prohibited experimental work using domesticated domesticated strains in plant-associated habitats. However, undomesticated/primary environmental isolates were shown to colonize plants, and provide increased protection against pathogens (Chen et al. 2013). Thus, the genetic traceability of this model organism offers an opportunity to identify the genetic linkage of antibiotic production and resistance with biocontrol properties. ESTABLISHING B. SUBTILIS AND B. AMYLOLIQUEFACIENS GENETICS The genome sequence of B. subtilis 168 was first published in 1996 by a consortium of mainly European and Japanese laboratories (Moszer, Kunst and Danchin 1996). This genome was entirely re‐sequenced 10 years later using next-generation sequencing methods (Barbe et al. 2009). Sequence annotations inevitably change with improvements in the identification of gene function resulting from the intense focus of research on this prominent model. Some genes were actually annotation artifacts, while novel genomic objects, in particular untranslated regulatory RNAs, are being discovered on a regular basis. The final annotation of the genome sequence, published in November 2017, included a large number of newly identified functions (including several unpublished experimentally established functions, and the discovery of new genomic objects with experimentally established functions). Relying strongly on annotations of B. subtilis, multiple genomes are now available for B. amyloliquefaciens (Chen et al. 2007). As the genomes of B. subtilis, B. amyloliquefaciens, B. velezensis and B. mojavensis are very closely related (Silva et al. 2019), functional studies in each model bacterium can easily be translated to many relevant biocontrol strains. Furthermore, all these beneficial plant microbiota members are genetically manipulatble. THE GENETICS OF ANTIBIOTIC PRODUCTION IN BACILLUS SUBTILIS AND RELATED SPECIES The regulation of antibiotic production is poorly characterized, as it is highly condition dependent (Nicolas et al. 2012) to allow microbial communities to successfully compete in a highly dynamic environment against different competitors. During competition, B. subtilis ecotypes can discriminate self from non-self. Although the genetic basis of self-discrimination is only partially resolved, self-produced antibacterials are involved in self-recognition (Stefanic et al. 2015; Lyons et al. 2016). The genome of Bacillus strains contain gene clusters that are involved in the synthesis of lipopeptides and polyketides, as well as those directing immunity against commonly produced Bacilli antibiotics [Fig. 1A, (Lyons et al. 2016; Cai et al. 2017; Nigris et al. 2018; Pinto et al 2018)]. Therefore, we will discuss in the function of antibiotic production genes, prior to discussing antibiotic resistance. Bacillus  subtilis biocontrol agents use a variety of mechanisms to target several plant pathogens; however, the most well-characterized antibiosis mechanisms are attributed to non-ribosomally produced cyclic lipopeptides (Stein 2005; Romero et al. 2007; Ongena and Jacques 2008). Lipopeptides, which are amphiphilic molecules with an amino or hydroxyl‐fatty acid integrated into a peptide moiety, interact with the biological membranes of microbial pathogens, inducing cell leakage and death (Romero et al. 2007; Zeriouh et al. 2011). These lipopeptides include bacillomycins and fengycins, which have direct antimicrobial activity, as well as surfactin, although its putative cytotoxic effect is controversial (Bais, Fall and Vivanco 2004; Zeriouh et al. 2014). Lipopeptides contribute to biocontrol through the following additional functions: (i) surfactin and fengycin activate the ISR in host plants (Garcia-Gutierrez et al. 2013), and (ii) surfactin, contributes to the colonization of plant roots (Bais, Fall and Vivanco 2004). In addition to lipopeptides, B. subtilis and B. amyloliquefaciens produce various antibacterial molecules, and their diverse repertoire is described below. SURFACTIN This ecologically important surfactant is produced by B. subtilis, B. amyloliquefaciens, B. velezensis and B. mojavensis. The production of this small cyclic lipopeptide is induced during the development of genetic competence (Magnuson, Solomon and Grossman 1994). The machinery for surfactin synthesis is encoded within the srfAA–AB–AC–AD operon (Kluge et al. 1988). Surfactin acts as for the ‘common good’ of the community members during collective motility (Kearns et al. 2004) and is also a powerful surfactant with antibacterial (Gonzalez et al. 2011) and antifungal properties (Falardeau et al. 2013). Surfactin is composed of an amphipathic, cyclic heptapeptide head group that is interlinked with a hydrophobic β-hydroxy fatty acid tail, comprising 12–16 carbon atoms (Avigad 1970, Hoefler et al. 2012; Watrous et al. 2012). These features enable the surfactin molecule to interact with, and disrupt the integrity of cellular membranes (Grau, Go and Ortiz 1999). Surfactin production is sensed in combination with additional environmental signals by a subgroup of the biofilm population that then produces the extracellular matrix (Chai et al. 2008; Lopez et al. 2009; Vlamakis et al. 2013). Interestingly, the metastable state of this molecule seems to be of critical importance for intra-genus interactions. A specific isomer of surfactin (C12) was found to be at the core of the antagonistic interaction with Bacillus simplex. In this study, interspecies competition resulted in selection for increased plasmid loss and increased the frequency of plasmidless isolates exhibiting altered production of secondary metabolites, including surfactin (Rosenberg et al. 2016). The use of genetically modified organisms for biocontrol is prohibited in many European facilities (Jones 2015); therefore, these results highlight a potential use of laboratory evolution to increase the efficiency of antibiotic production. Due to the properties of this surfactant, surfactin is also extremely potent against enveloped viruses such as the Ebola, Zika, Nipah, chikungunya, Una, Mayaro, Dugbe and Crimean-Congo hemorrhagic fever viruses (Yuan et al. 2018; Johnson et al. 2019). The same mechanisms are presumed to apply to enveloped plant viruses (Ibrahim, Odon and Kormelink 2019). BACILLAENE Bacillaene and dihydrobacillaene (Butcher et al. 2007; Straight et al. 2007), are polyketides synthesized by an enzymatic complex encoded in the pks gene cluster (Butcher et al. 2007; Straight et al. 2007). Bacillaene is a linear antimicrobial macrolide with two amide bonds and is synthesized by the PKSJLMNR cluster mega-complex, which is composed of 13 PKS and three NRPS modules in Bacillus species (Straight et al. 2007). The expression of pks genes requires the master regulator for biofilm formation, Spo0A and therefore promotes the competitiveness of biofilm communities (Vargas-Bautista, Rahlwes and Straight 2014). Bacillaene is a highly unstable inhibitor of protein synthesis and its antibacterial activities are mediated by selective inhibition of protein synthesis in prokaryotic pathogens. Bacillaene was indicated to protect B. subtilis during predator-prey interactions with myxococcus species (Muller et al. 2014). Interestingly, preliminary evidence suggests that the plant host can enhance the efficiency of the killing of Serratia plymuthica by B. subtilis by inducing bacillaene synthesis (Ogran et al. 2019), which is consistent with a known role for plant exudates in Spo0A regulation (Chen et al. 2012; Beauregard et al. 2013; Ganin et al. 2019). The impact of plant exudates on microbial competition resulted in a more favorable plant-associated community (Ogran et al. 2019). While the PKSJLMNR cluster is complex, and genetic manipulation to enhance its functions is complicated, these biosynthetic clusters are inducible by various community members (Vargas-Bautista, Rahlwes and Straight 2014) and plant secondary metabolites (Ogran et al. 2019). Therefore, the design of formulations and communities to enhance bacillaene and dihydrobacillaene production in the field seems feasible. BACILYSIN This non-ribosomal dipeptide is composed of L-alanine and amino acid L-anticapsin, and acts as an antibiotic with activities against a wide range of bacterial and fungal pathogens (Rajavel, Mitra and Gopal 2009). Its synthesis is controlled mainly by the bac operon (bacABCDE) and is regulated by other enzymes such as thymidylate synthase, homocysteine methyl transferase and the oligopeptide permeases (Inaoka et al. 2003). Oligopeptide permeases in Bacillus species are often involved in quorum-sensing by small inducing peptides (Auchtung, Lee and Grossman 2006). Therefore, bacilysin production is probably regulated via the quorum-sensing pathway (Hilton, Alaeddinoglu and Demain 1988; Karatas, Cetin and Ozcengiz 2003). Bacilysin production in Bacillus species is also affected by other environmental factors, such as media supplements or temperature (Ozcengiz and Alaeddinoglu 1991). This dipeptide undergoes peptidase-mediated proteolysis to release L-anticapsin, which is a competitive inhibitor of glucosamine synthase (Rajavel, Mitra and Gopal 2009). Bacilysin can also be produced as Chlorotetain, with unusual chlorine containing amino acid (Rapp et al. 1988; Phister, O'Sullivan and McKay 2004) ITURIN, BACILLOMYCIN D AND FENGYCIN (Nasir et al. 2013; Gu et al. 2017) are lipopeptides that exhibit a broad antimicrobial spectrum and exceptional surfactant activities in Bacillus. A total of four biosynthetic genes, ituA, ituB, ituC and ituD, encode the proteins involved in iturin biosynthesis (Feignier, Besson and Michel 1995; Rahman, Ano and Shoda 2006). Sporulation and germination halt the production of these lipopeptides (Gong et al. 2015) and surfactin enhances the biological properties of iturin A (Maget-Dana et al. 1992). Fengycin/plipastatin (Tsuge, Matsui and Itaya 2007) is a highly effective lipopeptide antibiotic produced by Bacillus species , which is composed of a β-hydroxy fatty acid and a linked peptide comprising 10 amino acids. As a typical biosurfactant, plipastatin targets the cell membrane (Lopez et al. 2009; Lopez and Kolter 2010). Fengycin is synthesized non-ribosomally by five fengycin synthetases (ppsA, ppsB, ppsC, ppsD and ppsE) that are regulated by DegQ, a master regulator which regulates the transition from a motile cell state to a biofilm-forming state (Tsuge et al. 1999). DegQ is activated by catabolite repression and is under the control of the DegSU two-component system. This regulation allows an increase in the rate of DegQ synthesis under conditions of nitrogen starvation (Tsuge et al. 1999), and can also be used to further enhance plipastatin production. RIBOSOMALLY SYNTHESIZED PEPTIDES The antibiotics subtilin (Qin et al. 2019) and subtilosin A (Babasaki et al. 1985; Marx et al. 2001; Shelburne et al. 2007) are ribosomally produced and post-translationally modified to generate bacteriocin antibiotics that exhibit potent activity against Gram-positive competitors and fungi. PRACTICAL APPLICATIONS FOR PLANT AND CROP PROTECTION As mentioned above, the antibiotics produced by the B. subtilis clade exhibit antibiosis properties of great relevance to the protection of the host. Surfactin production by B. subtilis, B. amyloliquefaciens, B. velezensis and B. mojavensis contribute to biocontrol activities and growth inhibition of prevalent plant pathogens (Souto et al. 2004; Grady et al. 2019): On Arabidopsis roots, surfactin promoted the competitiveness and biocontrol properties again the plant pathogen, Pseudomonas syringae(Bais, Fall and Vivanco2004), although this pathogen generally colonizes the leaves. On melon leaves, surfactin production was required to eliminate the fungi Podosphaera fusca and the plant pathogenic bacteria Pectobacterium carotovorum subsp. carotovorum and Xanthomonas campestris (Zeriouh et al. 2014). In cucumber cultivated in vitro, the same lipopeptide halted wilt disease by elimination of the fungi Fusarium (Snook et al. 2009; Jia et al. 2015). Furthermore, surfactin production inhibited bacterial fruit blotch (BFB) caused by the Gram-negative bacterium Acidovorax citrulli, which is a serious crop disease worldwide (Fan et al. 2017b). In all of the cases described here, the requirement for surfactin was demonstrated generically (by comparing the parental strain performance with its srf mutants) and/or biochemically (by application of purified surfactin). Bacillomycin D is am additional lipopeptide that has been confirmed to be involved in plant protection. This lipopeptide is closely related to iturin, which inhibits the formation and germination of Fusarium graminearum hyphae (Gu et al. 2017). Bacillomycin D was shown to antagonize the infection of F. graminearum on corn silks, wheat seedlings and wheat heads (Gu et al. 2017). Furthermore, several Bacillomycin producing Bacillus strains effectively inhibited a broad range of plant pathogens. Specific examples include Sclerotinia sclerotiorum, a pathogen of canola and wheat (Ramarathnam et al. 2007), Colletotrichum gloeosporioides, a pathogenic fungi with great adaptability to environmental changes (Luna-Bulbarela et al. 2018), Aspergillus niger (Li et al. 2016) and Mucor racemosus and F. oxysporum, which infect peaches (Li et al. 2016). Similarly, Iturin and fungycin contributed to biocontrol of citrus crops post-harvest (Arrebola, Jacobs and Korsten 2010) and prevented gray rot diseases in apples (Fan et al. 2017c). Although the ribosomally synthesized peptide bacilysin protected against bacterial leaf streak disease in rice by acting as a bactericidal agent, there is less direct evidence of its contribution to biocontrol efficiency of Bacillus subtilis and related species compared with lipopeptides. So far, it has been shown to disrupt the cell wall of the pathogens Xanthomonas oryzae (Wu et al. 2015) and Erwinia amylovora (Chen et al. 2009). In addition to their direct bactericidal roles, there is a growing evidence that these Bacillus antibiotics can contribute to plant growth via alternative mechanisms. On melon leaves, surfactin was essential for host colonization and promoted the assembly of the bacterial extracellular matrix (Zeriouh et al. 2014). Furthermore, pure fengycins and surfactins were sufficient to induce significant protective effects on beans as activators of the ISR, and their role as inducers of the host immune system was sufficient to explain the beneficial phenotypes of the producing strain. The induced immune resistance of the plant was achieved by activation of the host lipoxygenase pathway mediated by the microbial lipopeptides (Ongena et al. 2007). To summarize, antibiotic production is essential for rhizocompatibility, for the identification of optimal strains for plant and crop protection and for the design of minimal synthetic communities. This predictability is critically dependent on full elucidation of the mechanisms of antibiotic production. However, the production of antibiotics, as well as the continuous exposure to antibiotics produced by competitors, requires an equally profound understanding of the regulation and genetics of antibiotic resistance. The rhizosphere and the soil are not only rich sources of antimicrobial molecules, but also of antibiotic resistance regulatory networks, cassettes and genes. We will here explore the existing knowledge on these networks in Bacillus subtilis and related species. ANTIBIOTIC PRODUCTION BY COMPETITORS OF BACILLUS SPECIES IN THE RHIZOSPHERE The most prominent secondary metabolite producers in the soil are the Gram-positive, spore-forming, filamentous actinobacteria (actinomycetes), which have been utilized as the primary resource for the development of clinical antibiotics (Genilloud 2018). Within the actinomycetes, members of the genus Streptomyces account for 70–80% of the identified antibiotics. Gene clusters that occupy up to 6% of the genome encode secondary metabolite production in Streptomyces and most antibiotics are synthesized by NRPS or PKS/NRPS, as discussed above in relation to Bacillus subtilis (Traxler et al. 2013; Olanrewaju and Babalola 2019). Actinomycetes also produce a variety of cell envelope-targeting antibiotics. One NRPS-produced lipopeptide is daptomycin (Bertsche et al. 2013), which integrates into the bacterial membrane in a calcium-dependent manner, leading to depolarization of the membrane and extrusion of potassium ions. The glycopeptide vancomycin and the lipoglycopeptides teicoplanin and ramoplanin (and their analogues) have been isolated from actinomycetes and all inhibit peptidoglycan biosynthesis by interacting with lipid II (Citron et al. 2003). In the soil, actinomycetes are proficient synthesizers of β-lactam antibiotics (Stapley et al. 1972, Kovacevic and Miller 1991). Fungi also produce bacterial cell wall-targeting antibiotics, e.g. the ascomycetes Penicillium and Aspergillus, which produce β-lactams (Liras and Martin 2006). Thus, antibiotics are prevalent in the soil and rhizosphere, even in undisturbed settings. Here, similar to the situation in studies of antibiotic production, Bacillus genus can be used as a framework for the investigation of ARGs, their relation with Antibiotic Production Genes (APGs) and the mechanisms underlying their complementing functions as biocontrollers. ANTIBIOTIC RESISTANCE IN THE BACILLUS GENUS In general, resistance can be acquired through mutation and selection or by horizontal gene transfer, through which these resistance mechanisms also spread to pathogens in clinical settings. The natural genetic competence of B. subtilis clade, capable of the uptake of foreign genomic and plasmid DNA from its environment, makes this particular clade, particularly proficient in inquiring new gene clusters of ARGs from its environment (Dubnau 1991). ARGs encode for several specific general resistance mechanisms: (1) Modification of the drug target. For example, resistance against glycopeptides or lipoglycopeptides is mediated by the production of a lipid II ending in D-Ala-D-Lac or D-Ala-D-Ser, for which these antibiotics exhibit lower binding affinity than to the original D-Ala-D-Ala target. These modifications are introduced by D, D-peptidases or carboxypeptidases; (2) For peptidoglycan targeting antibiotics, bacteria can bypass a step in the biosynthesis pathway. For example, the transpeptidation reaction catalyzed by β-lactam-sensitive penicillin binding proteins (PBPs) can be bypassed by L, D-transpeptidases, which cross-link two stem-peptides at non-canonical sites and are insensitive to β-lactam inhibition; (3) Reduced membrane permeability or increased efflux through the action of efflux pumps. This mechanism of action is mainly relevant for Gram-negative bacteria, where an outer membrane protects the peptidoglycan. (4) Enzymatic inactivation of the antibiotic (Pontes et al. 2018). Two groups of commonly used ARGs seem to promote the competitiveness of Bacillus species within rhizosphere communities. These involve resistance versus polyketides and non-ribosomal peptides produced by related and unrelated species, and resistance versus beta-lactams produced by unrelated competitors. RESISTANCE TO NON-RIBOSOMAL PEPTIDES AND POLYKETIDES When Bacillus species sense antibiotics at sub-lethal concentrations, which are below the concentration that could cause severe damage to the cell envelope, the cell envelope response is activated. In bacteria, the σ factor is essential for promoter recognition and hence transcription initiation. The extracytoplasmic function σ factors (ECFs) enables the cells to respond appropriately to extracellular cues such as periplasmic stress, heat shock, iron transport or protein secretion (Lonetto et al. 1994; Pinto, Liu and Mascher 2019). Cell envelope stress inactivates the anti-σ factor and leads to release of the σ and activation of the regulon. The ECF sigma factors are responsible for the proper activation of most ARGs (Gebhard et al. 2014; Helmann 2016; Pinto, Liu and Mascher 2019; Pinto et al. 2019). In B. subtilis, four of the seven ECF sigma factors have characterized roles in antibiotic resistance: SigM, SigW, SigX and SigV and all are individually and collectively dispensable for growth and sporulation (Mascher, Hachmann and Helmann 2007). For example, SigW regulates several genes related to antibiotic resistance and its regulon includes approximately 60 genes, almost all with unknown function (Huang, Fredrick and Helmann 1998; Huang et al. 1999). Known regulon members include PspA, a homologue for phage-shock protein that stabilizes the membrane to protect cells versus lantibiotics, FabF, leading to changes in the membrane lipid composition, YvlC (a PspC homolog), SppA (a signal-peptide peptidase that cleaves peptides inside the membrane) and the YceGHI operon, granting resistance versus lantibiotics (Helmann 2016). Interestingly, the characterization of this regulon was made possible by competing B. subtilis with other Bacilli under laboratory conditions, an experiment that demonstrated the role played by SigW regulon in intrinsic resistance against competing strains that produce antibiotics. Specifically, five SigW‐dependent operons provided resistance to at least four different antimicrobial compounds including Streptomyces, which produced fosfomycin, an antibiotic used in the clinic, sublancin, an S-linked glycopeptide produced by Bacillus the cannibalism toxin SdpC and amylocyclicin, a small hydrophobic peptide made by B. amyloquifaciens (Butcher and Helmann 2006). In addition, several resistance genes are regulated independently from the ECF sigma factors, including the fosB fosfomycin‐resistance gene (Cao et al. 2001) and the pbpE gene encoding the penicillin‐binding protein (Popham and Setlow 1993). Genes encoding immunity against NRP antibiotics are often located on mobile elements and these can be ex-changed between closely related species in the rhizosphere. For example, the SPβ phage, encoding the production of sublancin as well as immunity for it, is not found in the natto strains of B. subtilis (Qiu et al. 2004). Similarity, an insertion of large antibiosis islands in a conserved insertion cite was demonstrated to encode the lantibiotics sericin or subtilin (in B. subtilis strain A1/3 and B. subtilis strain ATCC6633, respectively; Stein et al. 2002). In its natural habitat, B. subtilis strains are not only be in competition with phylogenetically unrelated soil microorganisms, but also with their own clade members that produce antibiotics against which they have no specific immunity. Thus, the general cell-wall stress response triggered by ECF sigma factors allows B. subtilis to compete for its niche and the biocontrol potential of a strain can be predicted based on the presence of the ECF σ controlled genes. B-LACTAM RESISTANCE IN RHIZOSPHERE BACILLI As mentioned previously, species of the Bacillus genus do not produce β-lactam antibiotics, but reside in an intimate association with their producers. Therefore, β-lactam resistance seems to be a fundamental requirement for success in the rhizosphere. In Bacillus subtilis, a single beta-lactamase, PenP, is expressed and contributes to ampicillin resistance. Interestingly, the expression of this enzyme is tightly regulated by non-toxic concentrations of cell wall stressors, including D-amino acids, and other cell wall-targeting antibiotics (Bucher et al. 2019). β-lactamases are poorly characterized as a feature of rhizocompatibility. Therefore, in a recent study, the genomes of Bacillus species from undisturbed soils were sequenced and up to five β-lactamases with differentiated activity spectra per genome were identified. In this study, β-lactamases were classified traditionally, either based on sequence similarity and structural homology (Ambler) or on the functional characteristics of the enzymes (Bush-Jacoby) β-lactam (Therrien and Levesque 2000). Among the 38 de novo sequenced genomes, at least one, and up to five, β-lactamase alleles were identified, with a total of 123 β-lactamase alleles (Bucher et al. 2019). The occurrence of β-lactamase genes in Bacillus species residing in undisturbed environments was demonstrated previously, primarily in Bacillus licheniformis (Salerno and Lampen 1986). However, this study indicated that the number and class of β-lactamase alleles was species-specific (Bucher et al. 2019). This study indicated that β-lactams are common in undisturbed environments and that successful soil and rhizosphere colonizers are preferentially resistant to these antibiotics. These findings are consistent with the growing evidence for natural reservoirs of ARGs in undisturbed environments (Butterworth et al. 1979; Cytryn 2013; Bucher et al. 2019; Vereecke et al. 2020). As the soil and rhizosphere select for resistance to non-ribosomal peptide, polyketides, lantibiotics and β-lactam antibiotics, one unexpected feature of the rhizosphere habitat is the leak of these resistance genes into the clinic. This leak is probably a combinatorial effect of the potential of sub-inhibitory concentrations of antibiotics in the soil communities that promote the development of antibiotic resistant bacteria, and the capacity of resistance determinants to transfer from anthropogenic sources (such as treated wastewater, manure or others sources) to human pathogens (Cytryn 2013). We suggest that similarily to APGs, ARGs are essential for the Bacillus species survival in the soil, rhizosphere and in similar competitive habitats. A FRAMEWORK FOR UTILIZING GENETIC TOOLS TO OPTIMIZE RHIZOSPHERE PERFORMANCE From the perspective of a microbial geneticist, direct evidence obtained using models must be considered to clarify the functions of Antibiotic Production Genes (APGs) and antibiotic resistance genes (ARGs) in the rhizosphere. The following workflow could be used: (a) Identify and delete the suspected antibiotic production and resistance genes clusters (e.g. APGs and ARGs, respectively) as discussed in the previous sections. (b) Compare the fitness of the parental strain and the mutants in competition with relevant competitors in vitro and in complex environments. (c) Elucidate the environmental and molecular regulation of the antibiotic production/resistance genes. As discussed in this review, B. subtilis, B. amyloliquefaciens, B. velezensis and B. mojavensis all provide the opportunity to follow this genetic framework. Once the molecular framework for the activation of these rhizocompetence genes is obtained, several techniques can be used to translate this knowledge into improved biocontrol performance. First, Bacillus strains or their spores (a small, resistant, dormant form of bacterial cells; Lopez, Vlamakis and Kolter 2009) can be applied to the plants with the appropriate supplements to induce the expression of antibiotic production and resistance genes, or with compatible beneficial competitors that induce their expression. Relevant stimulating competitors and metabolites were discussed throughout the review, and most likely, systematic screens of the expression of APGs and ARGs in lab settings (Fig. 1B) will increase their repertoire. Second, using transcriptional reporters frequently used to monitor APGs expression in B. subtilis (Lopez, Vlamakis and Kolter 2009) or Imaging mass spectrometry for their products (Liu et al. 2010), strains expressing more of these gene clusters can be identified or even evolved in the laboratory. These strains are most likely to compete better in the rhizosphere. Performing better in the plant rhizosphere should be considered together with the environmental outcome as these strains may also have deleterious effect on the diversity of the plant microbiome. This effect is expected to be less deleterious in conventional agricultural settings that often results in compromised microbiomes lacking ley beneficial species and taxa (Tuck et al. 2014). As of now, the literature supports that enriching the soil with Bacillus species results in a tolerable loss of biodiversity, together with disease suppression (Liu et al. 2020; Wang et al. 2020). In addition, the application of improved strains and consortia should be examined for plant growth promotion capacity, although enrichment of the microbiome with these PGP organisms is expected to result in an overall positive outcome (Huang et al. 2015; Gamez et al. 2019; Ali et al. 2020). Third, as the need for biocontrol strains starts to override the concerns related to the use of genetically modified organisms, the promoters of the clusters of APGs and, if required, corresponding ARGs, can be manipulated using the markerless processes. Alternatively, repressors of APGs and ARGs expression can be deleted. These antibiotic ‘super-producers’ that are also resistant to their own products can be used as optimized biocontrol agents. Most antibiotic production clusters also contain immunity genes, and therefore defect in their repressor (by environmental stimuli, lab evolution or mutagenesis) should generate super-producers to that resist their own products. The formation of ‘super-producers’ resistant to their antimicrobial products was demonstrated for B. subtilis, as an evolved isolate produced more surfactin and peptide toxins, with no deleterious effect of significance on its own growth (Rosenberg et al. 2016). Similar results were obtained for an abh mutant, mutated in a repressor controlling numerous antibacterial production and resistance genes (Strauch et al. 2007; Murray and Stanley-Wall 2010). While laboratory evolution of ‘super-producing’ communities is more time consuming than genetic manipulation, this approach may be more useful in countries where there is strong opposition to the use of genetically manipulatable organisms. Examples of the natural induction of antibiotic biosynthetic clusters and resistance genes of B. subtilis strains were discussed here and a suggested framework for the translation of the genetics of APGs and ARGs for optimized microbiome performance is described in Fig. 1B. SUMMARY Communities formed by bacteria on plant roots play an important role in ensuring the rhizosphere environment supports plant growth and fitness. The potential use of Bacillus species as protective biocontrol and growth promoting agents provides a solution to the immediate ecological requirement for an alternative to the overuse of environmentally harmful pesticides. However, much remains to be discovered regarding the mechanisms that govern the interactions between the host root, beneficial root-associated populations and their neighbor species in these complex communities. In the laboratory, fundamental research by multiple groups has provided deep insights into the mechanisms by which antibiotics contribute to the fitness of the genetically manipulatable Bacillus species, primarily by assessing the interaction of these beneficial biofilms with their competitors on the plant. These established experimental systems facilitate the combination of in-planta settings and in vitro systems to elucidate the function(s) and regulation of antibiotic production, its evolution and the beneficial effects of antibiotic-producing members of the plant microbiome. These mechanistic insights are essential to optimize the performance and economic sustainability of our reliance on soil microbiomes, especially Bacillus species, for biocontrol and plant growth promotion (Fig. 1). Unexpectedly, the same model can assist in providing feasible explanations for the mechanisms by which ARGs spread across environmental compartments and into the clinic, stabilize within a microbial population and eventually propagate on a global scale. Thinking of the rhizosphere as a complex habitat where a continuous arms race between APGs and ARGs takes place, may explain the evolution of the Bacillus genus and additional soil microbes. Currently, biological chemical-free agriculture is gaining support although the adoption of such strategies in response to the growing global need for the production of massive amounts of food is slow (Carvalho 2006). Considering the alarming increase in the use of pesticides, and the overall impact of anthropogenic actions on food security, our future sustainability depends on our capacity to utilize soil microbiomes for plant protection, without harming the diversity of this habitat (Berg et al. 2017; Bonner and Alavanja 2017). Using a hypothesis-driven framework to improve the performance of beneficial symbionts in general and biocontrol agents in particular, can be extremely useful (Fig. 1). Therefore, we cannot overestimate the importance of studying antibiosis in beneficial microbiomes. ACKNOWLEDGEMENTS The Kolodkin–Gal laboratory is supported by the Israel Science Foundation grant numbers 119/16 and ISF-JSPS 184/20 and Israel Ministry of Science—Tashtiot (Infrastructures)–123402 in Life Sciences and Biomedical Sciences. IKG is supported by an internal grant from the Estate of Albert Engleman provided by the Angel–Faivovich Fund for Ecological Research, and by a research grant from the Benoziyo Endowment Fund for the Advancement of Science. IKG is a recipient of the Rowland and Sylvia Career Development Chair. Conflict of interest We declare no conflict of interest. REFERENCES Adam E , Groenenboom AE, Kurm V et al. Controlling the microbiome: microhabitat adjustments for successful biocontrol strategies in soil and human gut . Front Microbiol . 2016 ; 7 : 1079 . Google Scholar Crossref Search ADS PubMed WorldCat Ali S , Hameed S, Shahid M et al. Functional characterization of potential PGPR exhibiting broad-spectrum antifungal activity . 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Google Scholar Crossref Search ADS PubMed WorldCat Author notes Current Affiliation: Department of Physics, The Chinese University of Hong Kong © FEMS 2020. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Harvesting the complex pathways of antibiotic production and resistance of soil bacilli for optimizing plant microbiome
JO - FEMS Microbiology Ecology
DO - 10.1093/femsec/fiaa142
DA - 2020-09-01
UR - https://www.deepdyve.com/lp/oxford-university-press/harvesting-the-complex-pathways-of-antibiotic-production-and-yCPsdVmRyR
VL - 96
IS - 9
DP - DeepDyve
ER -