scholarly journals Genomic and Chemical Investigation of Bioactive Secondary Metabolites From a Marine-Derived Fungus Penicillium steckii P2648

2021 ◽  
Vol 12 ◽  
Author(s):  
Guangshan Yao ◽  
Xiaofeng Chen ◽  
Huawei Zheng ◽  
Danhua Liao ◽  
Zhi Yu ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Gene Cluster ◽  
Pathogenic Bacteria ◽  
Biological Activities ◽  
Gene Clusters ◽  
Ionization Mass ◽  
Structural Determination ◽  
Isoquinoline Alkaloids ◽  
Biosynthesis Gene Cluster ◽  
Strong Activity

Marine fungi of the genus Penicillium are rich resources of secondary metabolites, showing a variety of biological activities. Our anti-bacterial screening revealed that the crude extract from a coral-derived fungus Penicillium steckii P2648 showed strong activity against some pathogenic bacteria. Genome sequencing and mining uncovered that there are 28 secondary metabolite gene clusters in P2648, potentially involved in the biosynthesis of antibacterial compounds. Chemical isolation and structural determination suggested citrinin is the dominant component of the crude extracts of P2648, and our further tests confirmed that citrinin showed excellent activities against various pathogenic bacteria. Moreover, the gene cluster containing a homolog of the polyketide synthase CitS was identified as the citrinin biosynthesis gene cluster through genetic analysis. Interestingly, three isoquinoline alkaloids were unexpectedly activated and isolated from the Δcits mutant and structural determination by using high-resolution electron spray ionization mass spectroscopy (HRESIMS), 1D, and 2D NMR. Further antibacterial assays displayed that compounds 1 and 2, but not compound 3, showed moderate activities against two antibiotic-resistant pathogenic bacteria with minimum inhibitory concentration (MIC) of 16–32 μg/ml. In conclusion, our results demonstrated that citrinin and isoquinoline alkaloids represent as the major antibacterial agents in the coral-associated fungus P. steckii P2648, and our genomic and chemical analyses present evidence in support of P. steckii P2648 as a potent natural products source for anti-bacterial drug discovery.

scholarly journals Overproduction of Ristomycin A by Activation of a Silent Gene Cluster in Amycolatopsis japonicum MG417-CF17

2014 ◽  
Vol 58 (10) ◽  
pp. 6185-6196 ◽  
Author(s):  
Marius Spohn ◽  
Norbert Kirchner ◽  
Andreas Kulik ◽  
Angelika Jochim ◽  
Felix Wolf ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Gene Cluster ◽  
High Performance ◽  
Pathogenic Bacteria ◽  
Genome Mining ◽  
Gene Clusters ◽  
Von Willebrand Disease ◽  
Biosynthesis Gene Cluster ◽  
Content Type ◽  
Bioinformatic Tools

ABSTRACTThe emergence of antibiotic-resistant pathogenic bacteria within the last decades is one reason for the urgent need for new antibacterial agents. A strategy to discover new anti-infective compounds is the evaluation of the genetic capacity of secondary metabolite producers and the activation of cryptic gene clusters (genome mining). One genus known for its potential to synthesize medically important products isAmycolatopsis. However,Amycolatopsis japonicumdoes not produce an antibiotic under standard laboratory conditions. In contrast to mostAmycolatopsisstrains,A. japonicumis genetically tractable with different methods. In order to activate a possible silent glycopeptide cluster, we introduced a gene encoding the transcriptional activator of balhimycin biosynthesis, thebbrgene fromAmycolatopsis balhimycina(bbrAba), intoA. japonicum. This resulted in the production of an antibiotically active compound. Following whole-genome sequencing ofA. japonicum, 29 cryptic gene clusters were identified by genome mining. One of these gene clusters is a putative glycopeptide biosynthesis gene cluster. Using bioinformatic tools, ristomycin (syn. ristocetin), a type III glycopeptide, which has antibacterial activity and which is used for the diagnosis of von Willebrand disease and Bernard-Soulier syndrome, was deduced as a possible product of the gene cluster. Chemical analyses by high-performance liquid chromatography and mass spectrometry (HPLC-MS), tandem mass spectrometry (MS/MS), and nuclear magnetic resonance (NMR) spectroscopy confirmed thein silicoprediction that the recombinantA. japonicum/pRM4-bbrAbasynthesizes ristomycin A.

scholarly journals Genomic and transcriptomic survey of an endophytic fungus Calcarisporium arbuscula NRRL 3705 and potential overview of its secondary metabolites

2019 ◽  
Author(s):  
Jintao Cheng ◽  
Fei Cao ◽  
Xinai Chen ◽  
Yongquan Li ◽  
Xuming Mao
Keyword(s):  
Secondary Metabolites ◽  
Gene Cluster ◽  
Endophytic Fungi ◽  
Single Molecule ◽  
Endophytic Fungus ◽  
Biological Activities ◽  
Housekeeping Genes ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters

Abstract Endophytic fungi can produce many active secondary metabolites, which are important resources of natural medicines. However, there is currently little understanding of endophytic fungi at the omics levels. Calcarisporium arbuscula , an endophytic fungus from the healthy fruit of russulaceae, can produce a variety of secondary metabolites with anti-cancer, anti-nematode and antibiotic bioactivities. Comprehensive survey of the endophytic fungi genome and transcriptome will help to understand their capacity to biosynthesize secondary metabolites and lay the foundation for the development of these precious resources. In this study，we reported the high-quality genome sequence of a strain C. arbuscula NRRL 3705 based on Single Molecule Real-Time sequencing technology. The genome of this fungus is over 45 Mb in size, relatively larger than other typical filamentous fungi, and comprises 10,001 predictable genes, encoding at least 762 secretory-proteins, 386 carbohydrate-active enzymes and 177 P450 enzymes. 398 virulence factors and 228 genes related to pathogen-host interactions were also predicted in this fungus. Moreover , 65 secondary metabolite biosynthetic gene clusters were revealed, including the gene cluster for mycotoxins aurovertins. In addition, several gene clusters were predicted to produce various mycotoxins, including aflatoxin, alternariol, destruxin, citrinin and isoflavipucine. Notably, two independent gene clusters were shown possibly involved in the biosynthesis of alternariol. Furthermore, RNA-Seq assay showed that only the expression of aurovertin gene cluster is much stronger than the housekeeping genes under laboratory conditions, consistent with that aurovertins are the predominant metabolites. The gene expression of the remaining 64 gene clusters for compound backbone biosynthesis was all lower than the housekeeping genes, which might partially explain poor production of other secondary metabolites in this fungus.Our omics data along with bioinformatics analysis indicated that C. arbuscula NRRL 3705 contains a large number of biosynthetic gene clusters and has a huge potential to produce profound secondary metabolites. This work also provides the basis for development of endophytic fungi as a new resource of natural products with promising biological activities.

scholarly journals Genomic and transcriptomic survey of an endophytic fungus Calcarisporium arbuscula NRRL 3705 and potential overview of its secondary metabolites

2020 ◽  
Author(s):  
Jintao Cheng ◽  
Fei Cao ◽  
Xinai Chen ◽  
Yongquan Li ◽  
Xuming Mao
Keyword(s):  
Secondary Metabolites ◽  
Gene Cluster ◽  
Endophytic Fungi ◽  
Single Molecule ◽  
Endophytic Fungus ◽  
Biological Activities ◽  
Housekeeping Genes ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters

Abstract Background: Endophytic fungi can produce many active secondary metabolites, which are important resources of natural medicines. However, there is currently little understanding of endophytic fungi at the omics levels. Calcarisporium arbuscula, an endophytic fungus from the healthy fruit of Russulaceae, can produce a variety of secondary metabolites with anti-cancer, anti-nematode and antibiotic bioactivities. Comprehensive survey of the endophytic fungi genome and transcriptome will help to understand their capacity to biosynthesize secondary metabolites and lay the foundation for the development of these precious resources.Results: In this study，we reported the high-quality genome sequence of a strain C. arbuscula NRRL 3705 based on Single Molecule Real-Time sequencing technology. The genome of this fungus is over 45 Mb in size, relatively larger than other typical filamentous fungi, and comprises 10,001 predictable genes, encoding at least 762 secretory-proteins, 386 carbohydrate-active enzymes and 177 P450 enzymes. 398 virulence factors and 228 genes related to pathogen-host interactions were also predicted in this fungus. Moreover, 65 secondary metabolite biosynthetic gene clusters were revealed, including the gene cluster for mycotoxins aurovertins. In addition, several gene clusters were predicted to produce various mycotoxins, including aflatoxin, alternariol, destruxin, citrinin and isoflavipucine. Notably, two independent gene clusters were shown possibly involved in the biosynthesis of alternariol. Furthermore, RNA-Seq assay showed that only the expression of aurovertin gene cluster is much stronger than the housekeeping genes under laboratory conditions, consistent with that aurovertins are the predominant metabolites. The gene expression of the remaining 64 gene clusters for compound backbone biosynthesis was all lower than the housekeeping genes, which might partially explain poor production of other secondary metabolites in this fungus.Conclusions: Our omics data along with bioinformatics analysis indicated that C. arbuscula NRRL 3705 contains a large number of biosynthetic gene clusters and has a huge potential to produce profound secondary metabolites. This work also provides the basis for development of endophytic fungi as a new resource of natural products with promising biological activities.

scholarly journals Characterization of the Role of para-Aminobenzoic Acid Biosynthesis in Folate Production by Lactococcus lactis

2007 ◽  
Vol 73 (8) ◽  
pp. 2673-2681 ◽  
Author(s):  
Arno Wegkamp ◽  
Wietske van Oorschot ◽  
Willem M. de Vos ◽  
Eddy J. Smid
Keyword(s):  
Gene Cluster ◽  
Lactococcus Lactis ◽  
Gene Clusters ◽  
Defined Medium ◽  
Biosynthesis Pathway ◽  
Chemically Defined Medium ◽  
Aminobenzoic Acid ◽  
Biosynthesis Gene Cluster ◽  
Gene Coding ◽  
Aba Biosynthesis

ABSTRACT The pab genes for para-aminobenzoic acid (pABA) biosynthesis in Lactococcus lactis were identified and characterized. In L. lactis NZ9000, only two of the three genes needed for pABA production were initially found. No gene coding for 4-amino-4-deoxychorismate lyase (pabC) was initially annotated, but detailed analysis revealed that pabC was fused with the 3′ end of the gene coding for chorismate synthetase component II (pabB). Therefore, we hypothesize that all three enzyme activities needed for pABA production are present in L. lactis, allowing for the production of pABA. Indeed, the overexpression of the pABA gene cluster in L. lactis resulted in elevated pABA pools, demonstrating that the genes are involved in the biosynthesis of pABA. Moreover, a pABA knockout (KO) strain lacking pabA and pabB C was constructed and shown to be unable to produce folate when cultivated in the absence of pABA. This KO strain was unable to grow in chemically defined medium lacking glycine, serine, nucleobases/nucleosides, and pABA. The addition of the purine guanine, adenine, xanthine, or inosine restored growth but not the production of folate. This suggests that, in the presence of purines, folate is not essential for the growth of L. lactis. It also shows that folate is not strictly required for the pyrimidine biosynthesis pathway. L. lactis strain NZ7024, overexpressing both the folate and pABA gene clusters, was found to produce 2.7 mg of folate/liter per optical density unit at 600 nm when the strain was grown on chemically defined medium without pABA. This is in sharp contrast to L. lactis strains overexpressing only one of the two gene clusters. Therefore, we conclude that elevated folate levels can be obtained only by the overexpression of folate combined with the overexpression of the pABA biosynthesis gene cluster, suggesting the need for a balanced carbon flux through the folate and pABA biosynthesis pathway in the wild-type strain.

scholarly journals Characterization of the Complete Zwittermicin A Biosynthesis Gene Cluster from Bacillus cereus

2008 ◽  
Vol 75 (4) ◽  
pp. 1144-1155 ◽  
Author(s):  
Brian M. Kevany ◽  
David A. Rasko ◽  
Michael G. Thomas
Keyword(s):  
Amino Acid ◽  
Bacillus Cereus ◽  
Gene Cluster ◽  
Biological Activities ◽  
Amino Sugar ◽  
Unusual Structure ◽  
Biosynthesis Gene Cluster ◽  
Biosynthesis Gene ◽  
Zwittermicin A ◽  
Biochemical Analyses

ABSTRACT Bacillus cereus UW85 produces the linear aminopolyol antibiotic zwittermicin A (ZmA). This antibiotic has diverse biological activities, such as suppression of disease in plants caused by protists, inhibition of fungal and bacterial growth, and amplification of the insecticidal activity of the toxin protein from Bacillus thuringiensis. ZmA has an unusual chemical structure that includes a d amino acid and ethanolamine and glycolyl moieties, as well as having an unusual terminal amide that is generated from the modification of the nonproteinogenic amino acid β-ureidoalanine. The diverse biological activities and unusual structure of ZmA have stimulated our efforts to understand how this antibiotic is biosynthesized. Here, we present the identification of the complete ZmA biosynthesis gene cluster from B. cereus UW85. A nearly identical gene cluster is identified on a plasmid from B. cereus AH1134, and we show that this strain is also capable of producing ZmA. Bioinformatics and biochemical analyses of the ZmA biosynthesis enzymes strongly suggest that ZmA is initially biosynthesized as part of a larger metabolite that is processed twice, resulting in the formation of ZmA and two additional metabolites. Additionally, we propose that the biosynthesis gene cluster for the production of the amino sugar kanosamine is contained within the ZmA biosynthesis gene cluster in B. cereus UW85.

scholarly journals Genome mining of a marine-derived Streptomyces sp. PDH23 isolated from sponge in Da Nang sea for secondary metabolite gene clusters

2021 ◽  
Vol 18 (4) ◽  
pp. 709-721
Author(s):  
Le Ngoc Giang ◽  
Le Thi Hong Minh ◽  
Vu Thi Quyen ◽  
Nguyen Mai Anh ◽  
Nguyen Thi Kim Cuc ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Antimicrobial Agents ◽  
Biological Activities ◽  
Wide Spectrum ◽  
Genome Mining ◽  
Gc Content ◽  
Gene Clusters ◽  
Gram Positive ◽  
16S Rrna Analysis ◽  
Streptomyces Sp

The streptomyces is one of the best characterized ubiquitous filamentous bacteria from the actinobacteriaclass. They are known to produce thousands of specialized metabolite biosynthesis gene clusters (SMBG). Their SMBG clusters have multiple activities ranging from antimicrobial, antitumor, antiviral and probiotic. Streptomyces strain and their isolates with interesting biological activities against gram-positive and gram-negative indicator strains was recently characterised. Currently, they are employed in more than half of all antibiotics used in human and veterinary medicine. With the increase in drug resistance bacteria, it is important to mine for new natural chemicals.In this study, screening via disk-diffusion agar method revealed that Streptomyces sp. PDH23 isolated from the Rhabdastrellaglobostellata marine sponge sample from Da Nang, Vietnam produce antimicrobial agents with a wide spectrum of activities. This species can produce highly active enzymes, which breakdown celluloses, amyloses and proteins. On top of that they are shown to restrict the grow of the gram positive Bacillus cereus ATCC14579 (BC), Staphylococcus aureus ATCC25923 (SA), the gram-negativeVibrio parahaemolyticus ATCC17802 (VP) and the Candida albicans ATCC10231 fungus (CA). They are antimethicillin-resistant S. aureus(MRSA) ATCC33591 andmethicillin-resistantS. epidermidis (MRSE) ATCC35984. The taxonomy of PDH23 was characterized using 16S rRNA analysis. Whole genome sequencing of PDH23 showed 8594820 base pairs with GC content of 72.03%. Mining of secondary metabolites reveals gene clusters responsible for the biosynthesis of known and/or novel secondary metabolites, including different types of terpene, NRPS-like , PKS, PKS-like, hglE-KS, betalactone, melanin, t1pks, t2pks, t3pks, nrps, indole, siderophore, bacteriocin, ectoine, butyrolactone, phenazine.

scholarly journals Genome mining and UHPLC-MS/MS illuminate the specificity of secondary metabolite synthetic gene clusters in Bacillus subtilis NCD-2

2020 ◽  
Author(s):  
Zhenhe Su ◽  
Xiuye Chen ◽  
Xiaomeng Liu ◽  
Qinggang Guo ◽  
Shezeng Li ◽  
...  
Keyword(s):  
Bacillus Subtilis ◽  
Secondary Metabolites ◽  
Secondary Metabolite ◽  
Biological Activities ◽  
Genome Mining ◽  
Gene Clusters ◽  
Synthetic Gene ◽  
Integrative Approach ◽  
Amino Acid Sequence Similarity ◽  
Genetic Characteristics

Abstract Background Bacillus subtilisstrain NCD-2 is anexcellent biocontrol agent against plant soil-borne diseases and shows broad-spectrum antifungal activities. This study aimed to explore all the secondary metabolite synthetic gene clusters and related bioactive compounds in NCD-2. An integrative approach, which coupled genome mining with structural identification technologies using ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry (UHPLC-MS/MS), was conducted to interpret the chemical origins of the significant biological activities in NCD-2. Results Genome mining revealed that NCD-2 contained nine gene clustershaving predicted functionsinvolving secondary metabolites with bioactive abilities. They encoded six known products-fengycin, surfactin, bacillaene, subtilosin, bacillibactin, and bacilysin-as well as three unknown products.Interestingly, the synthetic gene clusters for surfactin and fengycin showed 83% and 92% amino acid sequence similarity levels with the corresponding productsin Bacillus velezensisstrain FZB42. A further comparison of gene clusters encoding fengycin and surfactinrevealed that strain NCD-2 had lost thefenC and fenDgenes in the fengycinbiosynthetic operon, and that the surfactin synthetic enzyme-related gene srfAB was divided into two parts.Abioinformatics analysis showed that fenEAmay function as fenCD in synthesizing fengycinand that the structure of thisfengycin synthetic gene clusteris likely unique to NCD-2.Five kinds of fengycin,with 26 homologs, and surfactin,with 4 homologs,were detectedfrom strain NCD-2, which indicated the non-typical and unique nature of this fengycin biosynthetic gene cluster.To the best of our knowledge, this is the first report of a non-typical gene cluster related to fengycin synthesis. Conclusions The data provide the genetic characteristics of secondary metabolite synthetic gene clusters for fengycinand surfactin in B. subtilis NCD-2, including the unique synthetic mechanism for fengycin, and suggest that bioactive secondary metabolites explain the biological activities of NCD-2.

scholarly journals Expanded Natural Product Diversity Revealed by Analysis of Lanthipeptide-Like Gene Clusters in Actinobacteria

2015 ◽  
Vol 81 (13) ◽  
pp. 4339-4350 ◽  
Author(s):  
Qi Zhang ◽  
James R. Doroghazi ◽  
Xiling Zhao ◽  
Mark C. Walker ◽  
Wilfred A. van der Donk
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Gene Cluster ◽  
Posttranslational Modifications ◽  
Large Scale ◽  
Biological Activities ◽  
Gene Clusters ◽  
Chemical Diversity ◽  
Content Type ◽  
Modified Peptides

ABSTRACTLanthionine-containing peptides (lanthipeptides) are a rapidly growing family of polycyclic peptide natural products belonging to the large class of ribosomally synthesized and posttranslationally modified peptides (RiPPs). Lanthipeptides are widely distributed in taxonomically distant species, and their currently known biosynthetic systems and biological activities are diverse. Building on the recent natural product gene cluster family (GCF) project, we report here large-scale analysis of lanthipeptide-like biosynthetic gene clusters fromActinobacteria. Our analysis suggests that lanthipeptide biosynthetic pathways, and by extrapolation the natural products themselves, are much more diverse than currently appreciated and contain many different posttranslational modifications. Furthermore, lanthionine synthetases are much more diverse in sequence and domain topology than currently characterized systems, and they are used by the biosynthetic machineries for natural products other than lanthipeptides. The gene cluster families described here significantly expand the chemical diversity and biosynthetic repertoire of lanthionine-related natural products. Biosynthesis of these novel natural products likely involves unusual and unprecedented biochemistries, as illustrated by several examples discussed in this study. In addition, class IV lanthipeptide gene clusters are shown not to be silent, setting the stage to investigate their biological activities.

scholarly journals Chromatin-dependent regulation of secondary metabolite biosynthesis in fungi: is the picture complete?

2019 ◽  
Author(s):  
Jérôme Collemare ◽  
Michael F Seidl
Keyword(s):  
Secondary Metabolites ◽  
Secondary Metabolite ◽  
Biological Activities ◽  
Gene Clusters ◽  
Research Field ◽  
Chromatin Modifications ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Post Translational Modifications ◽  
Fungal Secondary Metabolites

ABSTRACTFungal secondary metabolites are small molecules that exhibit diverse biological activities exploited in medicine, industry and agriculture. Their biosynthesis is governed by co-expressed genes that often co-localize in gene clusters. Most of these secondary metabolite gene clusters are inactive under laboratory conditions, which is due to a tight transcriptional regulation. Modifications of chromatin, the complex of DNA and histone proteins influencing DNA accessibility, play an important role in this regulation. However, tinkering with well-characterised chemical and genetic modifications that affect chromatin alters the expression of only few biosynthetic gene clusters, and thus the regulation of the vast majority of biosynthetic pathways remains enigmatic. In the past, attempts to activate silent gene clusters in fungi mainly focused on histone acetylation and methylation, while in other eukaryotes many other post-translational modifications are involved in transcription regulation. Thus, how chromatin regulates the expression of gene clusters remains a largely unexplored research field. In this review, we argue that focusing on only few well-characterised chromatin modifications is significantly hampering our understanding of the chromatin-based regulation of biosynthetic gene clusters. Research on underexplored chromatin modifications and on the interplay between different modifications is timely to fully explore the largely untapped reservoir of fungal secondary metabolites.

scholarly journals A Two-Step Mechanism for the Activation of Actinorhodin Export and Resistance in Streptomyces coelicolor

mBio ◽  
2012 ◽  
Vol 3 (5) ◽  
Author(s):  
Ye Xu ◽  
Andrew Willems ◽  
Catherine Au-yeung ◽  
Kapil Tahlan ◽  
Justin R. Nodwell
Keyword(s):  
Secondary Metabolites ◽  
Pathogenic Bacteria ◽  
Streptomyces Coelicolor ◽  
Gene Clusters ◽  
Biosynthetic Gene Cluster ◽  
Resistance Mechanisms ◽  
Biosynthetic Gene ◽  
Content Type

ABSTRACT Many microorganisms produce secondary metabolites that have antibiotic activity. To avoid self-inhibition, the producing cells often encode cognate export and/or resistance mechanisms in the biosynthetic gene clusters for these molecules. Actinorhodin is a blue-pigmented antibiotic produced by Streptomyces coelicolor. The actAB operon, carried in the actinorhodin biosynthetic gene cluster, encodes two putative export pumps and is regulated by the transcriptional repressor protein ActR. In this work, we show that normal actinorhodin yields require actAB expression. Consistent with previous in vitro work, we show that both actinorhodin and its 3-ring biosynthetic intermediates [e.g., (S)-DNPA] can relieve repression of actAB by ActR in vivo. Importantly, an ActR mutant that interacts productively with (S)-DNPA but not with actinorhodin responds to the actinorhodin biosynthetic pathway with the induction of actAB and normal yields of actinorhodin. This suggests that the intermediates are sufficient to trigger the export genes in actinorhodin-producing cells. We further show that actinorhodin-producing cells can induce actAB expression in nonproducing cells; however, in this case actinorhodin is the most important signal. Finally, while the “intermediate-only” ActR mutant permits sufficient actAB expression for normal actinorhodin yields, this expression is short-lived. Sustained culture-wide expression requires a subsequent actinorhodin-mediated signaling step, and the defect in this response causes widespread cell death. These results are consistent with a two-step model for actinorhodin export and resistance where intermediates trigger initial expression for export from producing cells and actinorhodin then triggers sustained export gene expression that confers culture-wide resistance. IMPORTANCE Understanding the links between antibiotic resistance and biosynthesis is important for our efforts to manipulate secondary metabolism. For example, many secondary metabolites are produced at low levels; our work suggests that manipulating export might be one way to enhance yields of these molecules. It also suggests that understanding resistance will be relevant to the generation of novel secondary metabolites through the creation of synthetic secondary metabolic gene clusters. Finally, these cognate resistance mechanisms are related to mechanisms that arise in pathogenic bacteria, and understanding them is relevant to our ability to control microbial infections clinically.

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