Research

17 pages, 2091 KiB

Open AccessArticle

Genome-Guided Discovery of the First Myxobacterial Biarylitide Myxarylin Reveals Distinct C–N Biaryl Crosslinking in RiPP Biosynthesis

by Joachim J. Hug, Nicolas A. Frank, Christine Walt, Petra Šenica, Fabian Panter and Rolf Müller

Molecules 2021, 26(24), 7483; https://doi.org/10.3390/molecules26247483 - 10 Dec 2021

Cited by 24 | Viewed by 3880

Abstract

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a structurally diverse group of natural products. They feature a wide range of intriguing post-translational modifications, as exemplified by the biarylitides. These are a family of cyclic tripeptides found in Planomonospora, carrying a biaryl [...] Read more.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a structurally diverse group of natural products. They feature a wide range of intriguing post-translational modifications, as exemplified by the biarylitides. These are a family of cyclic tripeptides found in Planomonospora, carrying a biaryl linkage between two aromatic amino acids. Recent genomic analyses revealed that the minimal biosynthetic prerequisite of biarylitide biosynthesis consists of only one ribosomally synthesized pentapeptide precursor as the substrate and a modifying cytochrome-P450-dependent enzyme. In silico analyses revealed that minimal biarylitide RiPP clusters are widespread among natural product producers across phylogenetic borders, including myxobacteria. We report here the genome-guided discovery of the first myxobacterial biarylitide MeYLH, termed Myxarylin, from Pyxidicoccus fallax An d48. Myxarylin was found to be an N-methylated tripeptide that surprisingly exhibits a C–N biaryl crosslink. In contrast to Myxarylin, previously isolated biarylitides are N-acetylated tripeptides that feature a C–C biaryl crosslink. Furthermore, the formation of Myxarylin was confirmed by the heterologous expression of the identified biosynthetic genes in Myxococcus xanthus DK1622. These findings expand the structural and biosynthetic scope of biarylitide-type RiPPs and emphasize the distinct biochemistry found in the myxobacterial realm. Full article

(This article belongs to the Special Issue Microbial Natural Products in The Era of Genome- And Metabolome-Mining)

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26 pages, 3804 KiB

Open AccessArticle

Expanding the Myxochelin Natural Product Family by Nicotinic Acid Containing Congeners

by Nicolas A. Frank, Márió Széles, Sergi H. Akone, Sari Rasheed, Stephan Hüttel, Simon Frewert, Mostafa M. Hamed, Jennifer Herrmann, Sören M. M. Schuler, Anna K. H. Hirsch and Rolf Müller

Molecules 2021, 26(16), 4929; https://doi.org/10.3390/molecules26164929 - 14 Aug 2021

Cited by 5 | Viewed by 3473

Abstract

Myxobacteria represent a viable source of chemically diverse and biologically active secondary metabolites. The myxochelins are a well-studied family of catecholate-type siderophores produced by various myxobacterial strains. Here, we report the discovery, isolation, and structure elucidation of three new myxochelins N1–N3 from the [...] Read more.

Myxobacteria represent a viable source of chemically diverse and biologically active secondary metabolites. The myxochelins are a well-studied family of catecholate-type siderophores produced by various myxobacterial strains. Here, we report the discovery, isolation, and structure elucidation of three new myxochelins N1–N3 from the terrestrial myxobacterium Corallococcus sp. MCy9049, featuring an unusual nicotinic acid moiety. Precursor-directed biosynthesis (PDB) experiments and total synthesis were performed in order to confirm structures, improve access to pure compounds for bioactivity testing, and to devise a biosynthesis proposal. The combined evaluation of metabolome and genome data covering myxobacteria supports the notion that the new myxochelin congeners reported here are in fact frequent side products of the known myxochelin A biosynthetic pathway in myxobacteria. Full article

(This article belongs to the Special Issue Microbial Natural Products in The Era of Genome- And Metabolome-Mining)

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17 pages, 2448 KiB

Open AccessArticle

In Silico Analysis of P450s and Their Role in Secondary Metabolism in the Bacterial Class Gammaproteobacteria

by Ntombizethu Nokuphiwa Msomi, Tiara Padayachee, Nomfundo Nzuza, Puleng Rosinah Syed, Justyna Dorota Kryś, Wanping Chen, Dominik Gront, David R. Nelson and Khajamohiddin Syed

Molecules 2021, 26(6), 1538; https://doi.org/10.3390/molecules26061538 - 11 Mar 2021

Cited by 12 | Viewed by 2493

Abstract

The impact of lifestyle on shaping the genome content of an organism is a well-known phenomenon and cytochrome P450 enzymes (CYPs/P450s), heme-thiolate proteins that are ubiquitously present in organisms, are no exception. Recent studies focusing on a few bacterial species such as Streptomyces [...] Read more.

The impact of lifestyle on shaping the genome content of an organism is a well-known phenomenon and cytochrome P450 enzymes (CYPs/P450s), heme-thiolate proteins that are ubiquitously present in organisms, are no exception. Recent studies focusing on a few bacterial species such as Streptomyces, Mycobacterium, Cyanobacteria and Firmicutes revealed that the impact of lifestyle affected the P450 repertoire in these species. However, this phenomenon needs to be understood in other bacterial species. We therefore performed genome data mining, annotation, phylogenetic analysis of P450s and their role in secondary metabolism in the bacterial class Gammaproteobacteria. Genome-wide data mining for P450s in 1261 Gammaproteobacterial species belonging to 161 genera revealed that only 169 species belonging to 41 genera have P450s. A total of 277 P450s found in 169 species grouped into 84 P450 families and 105 P450 subfamilies, where 38 new P450 families were found. Only 18% of P450s were found to be involved in secondary metabolism in Gammaproteobacterial species, as observed in Firmicutes as well. The pathogenic or commensal lifestyle of Gammaproteobacterial species influences them to such an extent that they have the lowest number of P450s compared to other bacterial species, indicating the impact of lifestyle on shaping the P450 repertoire. This study is the first report on comprehensive analysis of P450s in Gammaproteobacteria. Full article

(This article belongs to the Special Issue Microbial Natural Products in The Era of Genome- And Metabolome-Mining)

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19 pages, 14127 KiB

Open AccessArticle

Genomics-Driven Activation of Silent Biosynthetic Gene Clusters in Burkholderia gladioli by Screening Recombineering System

by Hanna Chen, Tao Sun, Xianping Bai, Jie Yang, Fu Yan, Lei Yu, Qiang Tu, Aiying Li, Yajie Tang, Youming Zhang, Xiaoying Bian and Haibo Zhou

Molecules 2021, 26(3), 700; https://doi.org/10.3390/molecules26030700 - 29 Jan 2021

Cited by 11 | Viewed by 3199

Abstract

The Burkholderia genus possesses ecological and metabolic diversities. A large number of silent biosynthetic gene clusters (BGCs) in the Burkholderia genome remain uncharacterized and represent a promising resource for new natural product discovery. However, exploitation of the metabolomic potential of Burkholderia is limited [...] Read more.

The Burkholderia genus possesses ecological and metabolic diversities. A large number of silent biosynthetic gene clusters (BGCs) in the Burkholderia genome remain uncharacterized and represent a promising resource for new natural product discovery. However, exploitation of the metabolomic potential of Burkholderia is limited by the absence of efficient genetic manipulation tools. Here, we screened a bacteriophage recombinase system Redγ-BAS, which was functional for genome modification in the plant pathogen Burkholderia gladioli ATCC 10248. By using this recombineering tool, the constitutive promoters were precisely inserted in the genome, leading to activation of two silent nonribosomal peptide synthetase gene clusters (bgdd and hgdd) and production of corresponding new classes of lipopeptides, burriogladiodins A–H (1–8) and haereogladiodins A–B (9–10). Structure elucidation revealed an unnatural amino acid Z- dehydrobutyrine (Dhb) in 1–8 and an E-Dhb in 9–10. Notably, compounds 2–4 and 9 feature an unusual threonine tag that is longer than the predicted collinearity assembly lines. The structural diversity of burriogladiodins was derived from the relaxed substrate specificity of the fifth adenylation domain as well as chain termination conducted by water or threonine. The recombinase-mediating genome editing system is not only applicable in B. gladioli, but also possesses great potential for mining meaningful silent gene clusters from other Burkholderia species. Full article

(This article belongs to the Special Issue Microbial Natural Products in The Era of Genome- And Metabolome-Mining)

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7 pages, 947 KiB

Open AccessCommunication

SYN-View: A Phylogeny-Based Synteny Exploration Tool for the Identification of Gene Clusters Linked to Antibiotic Resistance

by Jason Stahlecker, Erik Mingyar, Nadine Ziemert and Mehmet Direnç Mungan

Molecules 2021, 26(1), 144; https://doi.org/10.3390/molecules26010144 - 31 Dec 2020

Cited by 7 | Viewed by 3952

Abstract

The development of new antibacterial drugs has become one of the most important tasks of the century in order to overcome the posing threat of drug resistance in pathogenic bacteria. Many antibiotics originate from natural products produced by various microorganisms. Over the last [...] Read more.

The development of new antibacterial drugs has become one of the most important tasks of the century in order to overcome the posing threat of drug resistance in pathogenic bacteria. Many antibiotics originate from natural products produced by various microorganisms. Over the last decades, bioinformatical approaches have facilitated the discovery and characterization of these small compounds using genome mining methodologies. A key part of this process is the identification of the most promising biosynthetic gene clusters (BGCs), which encode novel natural products. In 2017, the Antibiotic Resistant Target Seeker (ARTS) was developed in order to enable an automated target-directed genome mining approach. ARTS identifies possible resistant target genes within antibiotic gene clusters, in order to detect promising BGCs encoding antibiotics with novel modes of action. Although ARTS can predict promising targets based on multiple criteria, it provides little information about the cluster structures of possible resistant genes. Here, we present SYN-view. Based on a phylogenetic approach, SYN-view allows for easy comparison of gene clusters of interest and distinguishing genes with regular housekeeping functions from genes functioning as antibiotic resistant targets. Our aim is to implement our proposed method into the ARTS web-server, further improving the target-directed genome mining strategy of the ARTS pipeline. Full article

(This article belongs to the Special Issue Microbial Natural Products in The Era of Genome- And Metabolome-Mining)

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9 pages, 1666 KiB

Open AccessArticle

Genome Mining Reveals Two Missing CrtP and AldH Enzymes in the C30 Carotenoid Biosynthesis Pathway in Planococcus faecalis AJ003^T

by Jun Ho Lee, Jin Won Kim and Pyung Cheon Lee

Molecules 2020, 25(24), 5892; https://doi.org/10.3390/molecules25245892 - 12 Dec 2020

Cited by 10 | Viewed by 2081

Abstract

Planococcus faecalis AJ003^T produces glycosyl-4,4′-diaponeurosporen-4′-ol-4-oic acid as its main carotenoid. Five carotenoid pathway genes were presumed to be present in the genome of P. faecalis AJ003^T; however, 4,4-diaponeurosporene oxidase (CrtP) was non-functional, and a gene encoding aldehyde dehydrogenase (AldH) was [...] Read more.

Planococcus faecalis AJ003^T produces glycosyl-4,4′-diaponeurosporen-4′-ol-4-oic acid as its main carotenoid. Five carotenoid pathway genes were presumed to be present in the genome of P. faecalis AJ003^T; however, 4,4-diaponeurosporene oxidase (CrtP) was non-functional, and a gene encoding aldehyde dehydrogenase (AldH) was not identified. In the present study, a genome mining approach identified two missing enzymes, CrtP2 and AldH2454, in the glycosyl-4,4′-diaponeurosporen-4′-ol-4-oic acid biosynthetic pathway. Moreover, CrtP2 and AldH enzymes were functional in heterologous Escherichia coli and generated two carotenoid aldehydes (4,4′-diapolycopene-dial and 4,4′-diaponeurosporene-4-al) and two carotenoid carboxylic acids (4,4′-diaponeurosporenoic acid and 4,4′-diapolycopenoic acid). Furthermore, the genes encoding CrtP2 and AldH2454 were located at a distance the carotenoid gene cluster of P. faecalis. Full article

(This article belongs to the Special Issue Microbial Natural Products in The Era of Genome- And Metabolome-Mining)

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18 pages, 1775 KiB

Open AccessArticle

Macrooxazoles A–D, New 2,5-Disubstituted Oxazole-4-Carboxylic Acid Derivatives from the Plant Pathogenic Fungus Phoma macrostoma

by Blondelle Matio Kemkuignou, Laura Treiber, Haoxuan Zeng, Hedda Schrey, Rainer Schobert and Marc Stadler

Molecules 2020, 25(23), 5497; https://doi.org/10.3390/molecules25235497 - 24 Nov 2020

Cited by 20 | Viewed by 3094

Abstract

In our ongoing search for new bioactive fungal metabolites, four previously undescribed oxazole carboxylic acid derivatives (1–4) for which we proposed the trivial names macrooxazoles A–D together with two known tetramic acids (5–6) were isolated [...] Read more.

In our ongoing search for new bioactive fungal metabolites, four previously undescribed oxazole carboxylic acid derivatives (1–4) for which we proposed the trivial names macrooxazoles A–D together with two known tetramic acids (5–6) were isolated from the plant pathogenic fungus Phoma macrostoma. Their structures were elucidated based on high-resolution mass spectrometry (HR-MS) and nuclear magnetic resonance (NMR) spectroscopy. The hitherto unclear structure of macrocidin Z (6) was also confirmed by its first total synthesis. The isolated compounds were evaluated for their antimicrobial activities against a panel of bacteria and fungi. Cytotoxic and anti-biofilm activities of the isolates are also reported herein. The new compound 3 exhibited weak-to-moderate antimicrobial activity as well as the known macrocidins 5 and 6. Only the mixture of compounds 2 and 4 (ratio 1:2) showed weak cytotoxic activity against the tested cancer cell lines with an IC₅₀ of 23 µg/mL. Moreover, the new compounds 2 and 3, as well as the known compounds 5 and 6, interfered with the biofilm formation of Staphylococcus aureus, inhibiting 65%, 75%, 79%, and 76% of biofilm at 250 µg/mL, respectively. Compounds 5 and 6 also exhibited moderate activity against S. aureus preformed biofilm with the highest inhibition percentage of 75% and 73% at 250 µg/mL, respectively. Full article

(This article belongs to the Special Issue Microbial Natural Products in The Era of Genome- And Metabolome-Mining)

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11 pages, 946 KiB

Open AccessArticle

Loseolamycins: A Group of New Bioactive Alkylresorcinols Produced after Heterologous Expression of a Type III PKS from Micromonospora endolithica

by Constanze Lasch, Nils Gummerlich, Maksym Myronovskyi, Anja Palusczak, Josef Zapp and Andriy Luzhetskyy

Molecules 2020, 25(20), 4594; https://doi.org/10.3390/molecules25204594 - 09 Oct 2020

Cited by 7 | Viewed by 2314

Abstract

Natural products are a valuable source of biologically active compounds with potential applications in medicine and agriculture. Unprecedented scaffold diversity of natural products and biocatalysts from their biosynthetic pathways are of fundamental importance. Heterologous expression and refactoring of natural product biosynthetic pathways are [...] Read more.

Natural products are a valuable source of biologically active compounds with potential applications in medicine and agriculture. Unprecedented scaffold diversity of natural products and biocatalysts from their biosynthetic pathways are of fundamental importance. Heterologous expression and refactoring of natural product biosynthetic pathways are generally regarded as a promising approach to discover new secondary metabolites of microbial origin. Here, we present the identification of a new group of alkylresorcinols after transcriptional activation and heterologous expression of the type III polyketide synthase of Micromonospora endolithica. The most abundant compounds loseolamycins A1 and A2 have been purified and their structures were elucidated by NMR. Loseolamycins contain an unusual branched hydroxylated aliphatic chain which is provided by the host metabolism and is incorporated as a starter fatty acid unit. The isolated loseolamycins show activity against gram-positive bacteria and inhibit the growth of the monocot weed Agrostis stolonifera in a germination assay. The biosynthetic pathway leading to the production of loseolamycins is proposed in this paper. Full article

(This article belongs to the Special Issue Microbial Natural Products in The Era of Genome- And Metabolome-Mining)

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16 pages, 1252 KiB

Open AccessArticle

Genome-Based Insights into the Production of Carotenoids by Antarctic Bacteria, Planococcus sp. ANT_H30 and Rhodococcus sp. ANT_H53B

by Michal Styczynski, Agata Rogowska, Katarzyna Gieczewska, Maciej Garstka, Anna Szakiel and Lukasz Dziewit

Molecules 2020, 25(19), 4357; https://doi.org/10.3390/molecules25194357 - 23 Sep 2020

Cited by 15 | Viewed by 4037

Abstract

Antarctic regions are characterized by low temperatures and strong UV radiation. This harsh environment is inhabited by psychrophilic and psychrotolerant organisms, which have developed several adaptive features. In this study, we analyzed two Antarctic bacterial strains, Planococcus sp. ANT_H30 and Rhodococcus sp. ANT_H53B. [...] Read more.

Antarctic regions are characterized by low temperatures and strong UV radiation. This harsh environment is inhabited by psychrophilic and psychrotolerant organisms, which have developed several adaptive features. In this study, we analyzed two Antarctic bacterial strains, Planococcus sp. ANT_H30 and Rhodococcus sp. ANT_H53B. The physiological analysis of these strains revealed their potential to produce various biotechnologically valuable secondary metabolites, including surfactants, siderophores, and orange pigments. The genomic characterization of ANT_H30 and ANT_H53B allowed the identification of genes responsible for the production of carotenoids and the in silico reconstruction of the pigment biosynthesis pathways. The complex manual annotation of the bacterial genomes revealed the metabolic potential to degrade a wide variety of compounds, including xenobiotics and waste materials. Carotenoids produced by these bacteria were analyzed chromatographically, and we proved their activity as scavengers of free radicals. The quantity of crude carotenoid extracts produced at two temperatures using various media was also determined. This was a step toward the optimization of carotenoid production by Antarctic bacteria on a larger scale. Full article

(This article belongs to the Special Issue Microbial Natural Products in The Era of Genome- And Metabolome-Mining)

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18 pages, 2777 KiB

Open AccessArticle

p-Aminophenylalanine Involved in the Biosynthesis of Antitumor Dnacin B1 for Quinone Moiety Formation

by Xiaojing Hu, Xing Li, Yong Sheng, Hengyu Wang, Xiaobin Li, Yixin Ou, Zixin Deng, Linquan Bai and Qianjin Kang

Molecules 2020, 25(18), 4186; https://doi.org/10.3390/molecules25184186 - 12 Sep 2020

Cited by 3 | Viewed by 2695

Abstract

Actinosynnema species produce diverse natural products with important biological activities, which represent an important resource of antibiotic discovery. Advances in genome sequencing and bioinformatics tools have accelerated the exploration of the biosynthetic gene clusters (BGCs) encoding natural products. Herein, the completed BGCs of [...] Read more.

Actinosynnema species produce diverse natural products with important biological activities, which represent an important resource of antibiotic discovery. Advances in genome sequencing and bioinformatics tools have accelerated the exploration of the biosynthetic gene clusters (BGCs) encoding natural products. Herein, the completed BGCs of dnacin B1 were first discovered in two Actinosynnema pretiosum subsp. auranticum strains DSM 44131^T (hereafter abbreviated as strain DSM 44131^T) and X47 by comparative genome mining strategy. The BGC for dnacin B1 contains 41 ORFs and spans a 66.9 kb DNA region in strain DSM 44131^T. Its involvement in dnacin B1 biosynthesis was identified through the deletion of a 9.7 kb region. Based on the functional gene analysis, we proposed the biosynthetic pathway for dnacin B1. Moreover, p-amino-phenylalanine (PAPA) unit was found to be the dnacin B1 precursor for the quinone moiety formation, and this was confirmed by heterologous expression of dinV, dinE and dinF in Escherichia coli. Furthermore, nine potential PAPA aminotransferases (APAT) from the genome of strain DSM 44131^T were explored and expressed. Biochemical evaluation of their amino group transformation ability was carried out with p-amino-phenylpyruvic acid (PAPP) or PAPA as the substrate for the final product formation. Two of those, APAT4 and APAT9, displayed intriguing aminotransferase ability for the formation of PAPA. The proposed dnacin B1 biosynthetic machinery and PAPA biosynthetic investigations not only enriched the knowledge of tetrahydroisoquinoline (THIQ) biosynthesis, but also provided PAPA building blocks to generate their structurally unique homologues. Full article

(This article belongs to the Special Issue Microbial Natural Products in The Era of Genome- And Metabolome-Mining)

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17 pages, 2707 KiB

Open AccessArticle

2-Hydroxysorangiadenosine: Structure and Biosynthesis of a Myxobacterial Sesquiterpene–Nucleoside

by Dorothy A. Okoth, Joachim J. Hug, Ronald Garcia, Cathrin Spröer, Jörg Overmann and Rolf Müller

Molecules 2020, 25(11), 2676; https://doi.org/10.3390/molecules25112676 - 09 Jun 2020

Cited by 9 | Viewed by 3619

Abstract

Myxobacteria represent an under-investigated source for biologically active natural products featuring intriguing structural moieties with potential applications, e.g., in the pharmaceutical industry. Sorangiadenosine and the here-discovered 2-hydroxysorangiadenosine are myxobacterial sesquiterpene–nucleosides with an unusual structural moiety, a bicyclic eudesmane-type sesquiterpene. As the biosynthesis of [...] Read more.

Myxobacteria represent an under-investigated source for biologically active natural products featuring intriguing structural moieties with potential applications, e.g., in the pharmaceutical industry. Sorangiadenosine and the here-discovered 2-hydroxysorangiadenosine are myxobacterial sesquiterpene–nucleosides with an unusual structural moiety, a bicyclic eudesmane-type sesquiterpene. As the biosynthesis of these rare terpene–nucleoside hybrid natural products remains elusive, we investigated secondary metabolomes and genomes of several 2-hydroxysorangiadenosine-producing myxobacteria. We report the isolation and full structure elucidation of 2-hydroxysorangiadenosine and its cytotoxic and antibiotic activities and propose a biosynthetic pathway in the myxobacterium Vitiosangium cumulatum MCy10943^T. Full article

(This article belongs to the Special Issue Microbial Natural Products in The Era of Genome- And Metabolome-Mining)

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11 pages, 2205 KiB

Open AccessArticle

Chemical, Bioactivity, and Biosynthetic Screening of Epiphytic Fungus Zasmidium pseudotsugae

by Gisela A. González-Montiel, Elizabeth N. Kaweesa, Nicolas Feau, Richard C. Hamelin, Jeffrey K. Stone and Sandra Loesgen

Molecules 2020, 25(10), 2358; https://doi.org/10.3390/molecules25102358 - 19 May 2020

Cited by 7 | Viewed by 3280

Abstract

We report the first secondary metabolite, 8,8′-bijuglone, obtained from pure cultures of the slow growing Douglas fir- (Pseudotsuga menziesii var. menziesii) foliage-associated fungus Zasmidium pseudotsugae. The quinone was characterized using extensive LC/MS and NMR-based spectroscopic methods. 8,8′-Bijuglone exhibited moderate antibiotic [...] Read more.

We report the first secondary metabolite, 8,8′-bijuglone, obtained from pure cultures of the slow growing Douglas fir- (Pseudotsuga menziesii var. menziesii) foliage-associated fungus Zasmidium pseudotsugae. The quinone was characterized using extensive LC/MS and NMR-based spectroscopic methods. 8,8′-Bijuglone exhibited moderate antibiotic activity against Gram-positive pathogens and weak cytotoxic activity in the NCI-60 cell line panel and in our in-house human colon carcinoma (HCT-116) cell line. An analysis of the fungal genome sequence to assess its metabolic potential was implemented using the bioinformatic tool antiSMASH. In total, 36 putative biosynthetic gene clusters were found with a majority encoding for polyketides (17), followed by non-ribosomal peptides (14), terpenes (2), ribosomal peptides (1), and compounds with mixed biosynthetic origin (2). This study demonstrates that foliage associated fungi of conifers produce antimicrobial metabolites and suggests this guild of fungi may present a rich source of novel molecules. Full article

(This article belongs to the Special Issue Microbial Natural Products in The Era of Genome- And Metabolome-Mining)

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10 pages, 1015 KiB

Open AccessArticle

LeTetR Positively Regulates 3-Hydroxylation of the Antifungal HSAF and Its Analogs in Lysobacter enzymogenes OH11

by Lingjun Yu, Vimmy Khetrapal, Fengquan Liu and Liangcheng Du

Molecules 2020, 25(10), 2286; https://doi.org/10.3390/molecules25102286 - 13 May 2020

Cited by 4 | Viewed by 2512

Abstract

The biocontrol agent Lysobacter enzymogenes OH11 produces several structurally distinct antibiotic compounds, including the antifungal HSAF (Heat Stable Antifungal Factor) and alteramides, along with their 3-dehydroxyl precursors (3-deOH). We previously showed that the 3-hydroxylation is the final step of the biosynthesis and is [...] Read more.

The biocontrol agent Lysobacter enzymogenes OH11 produces several structurally distinct antibiotic compounds, including the antifungal HSAF (Heat Stable Antifungal Factor) and alteramides, along with their 3-dehydroxyl precursors (3-deOH). We previously showed that the 3-hydroxylation is the final step of the biosynthesis and is also a key structural moiety for the antifungal activity. However, the procedure through which OH11 regulates the 3-hydroxylation is still not clear. In OH11, the gene orf3232 was predicted to encode a TetR regulator (LeTetR) with unknown function. Here, we deleted orf3232 and found that the LeTetR mutant produced very little HSAF and alteramides, while the 3-deOH compounds were not significantly affected. The production of HSAF and alteramides was restored in orf3232-complemented mutant. qRT-PCR showed that the deletion of orf3232 impaired the transcription of a putative fatty acid hydroxylase gene, orf2195, but did not directly affect the expression of the HSAF biosynthetic gene cluster (hsaf). When an enzyme extract from E. coli expressing the fatty acid hydroxylase gene, hsaf-orf7, was added to the LeTetR mutant, the production of HSAF and alteramides increased by 13–14 fold. This study revealed a rare function of the TetR family regulator, which positively controls the final step of the antifungal biosynthesis and thus controls the antifungal activity of the biocontrol agent. Full article

(This article belongs to the Special Issue Microbial Natural Products in The Era of Genome- And Metabolome-Mining)

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