Dataset Information

Activation of Cryptic Antibiotic Biosynthetic Gene Clusters Guided by RNA-seq Data from Both Streptomyces ansochromogenes and ΔwblA.

ABSTRACT: With the increase of drug resistance caused by the improper use and abuse of antibiotics, human beings are facing a global health crisis. Sequencing of Streptomyces genomes revealed the presence of an important reservoir of secondary metabolic gene clusters for previously unsuspected products with potentially valuable bioactivity. It has therefore become necessary to activate these cryptic pathways through various strategies. Here, we used RNA-seq data to perform a comparative transcriptome analysis of Streptomyces ansochromogenes (wild-type, WT) and its global regulatory gene disruption mutant ΔwblA, in which some differentially expressed genes are associated with the abolished nikkomycin biosynthesis and activated tylosin analogue compounds (TACs) production, and also with the oviedomycin production that is induced by the genetic manipulation of two differentially expressed genes (san7324 and san7324L) encoding RsbR. These results provide a significant clue for the discovery of new drug candidates and the activation of cryptic biosynthetic gene clusters.

SUBMITTER: Li Y

PROVIDER: S-EPMC8465540 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Publications

Activation of Cryptic Antibiotic Biosynthetic Gene Clusters Guided by RNA-seq Data from Both <i>Streptomyces ansochromogenes</i> and ΔwblA.

Li Yue Y Yu Haiying H Guan Hanye H Li Jingjing J Zhang Jihui J Xiang Hua H Li Jine J Tan Huarong H

Antibiotics (Basel, Switzerland) 20210910 9

With the increase of drug resistance caused by the improper use and abuse of antibiotics, human beings are facing a global health crisis. Sequencing of <i>Streptomyces</i> genomes revealed the presence of an important reservoir of secondary metabolic gene clusters for previously unsuspected products with potentially valuable bioactivity. It has therefore become necessary to activate these cryptic pathways through various strategies. Here, we used RNA-seq data to perform a comparative transcripto ...[more]

PMID: 34572679

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Project description:Streptomyces lividans is a suitable host for the heterologous expression of biosynthetic gene clusters (BGCs) from actinomycetes to discover "cryptic" secondary metabolites. To improve the heterologous expression of BGCs, herein we optimized S. lividans strain SBT5 via the stepwise integration of three global regulatory genes and two codon-optimized multi-drug efflux pump genes and deletion of a negative regulatory gene, yielding four engineered strains. All optimization steps were observed to promote the heterologous production of polyketides, non-ribosomal peptides, and hybrid antibiotics. The production increments of these optimization steps were additional, so that the antibiotic yields were several times or even dozens of times higher than the parent strain SBT5 when the final optimized strain, S. lividans LJ1018, was used as the heterologous expression host. The heterologous production of these antibiotics in S. lividans LJ1018 and GX28 was also much higher than in the strains from which the BGCs were isolated. S. lividans LJ1018 and GX28 markedly promoted the heterologous production of secondary metabolites, without requiring manipulation of gene expression components such as promoters on individual gene clusters. Therefore, these strains are well-suited as heterologous expression hosts for secondary metabolic BGCs. In addition, we successfully conducted high-throughput library expression and functional screening (LEXAS) of one bacterial artificial chromosome library and two cosmid libraries of three Streptomyces genomes using S. lividans GX28 as the library-expression host. The LEXAS experiments identified clones carrying intact BGCs sufficient for the heterologous production of piericidin A1, murayaquinone, actinomycin D, and dehydrorabelomycin. Notably, due to lower antibiotic production, the piericidin A1 BGC had been overlooked in a previous LEXAS screening using S. lividans SBT5 as the expression host. These results demonstrate the feasibility and superiority of S. lividans GX28 as a host for high-throughput screening of genomic libraries to mine cryptic BGCs and bioactive compounds.

Dataset Information

Activation of Cryptic Antibiotic Biosynthetic Gene Clusters Guided by RNA-seq Data from Both Streptomyces ansochromogenes and ΔwblA.

Publications

Activation of Cryptic Antibiotic Biosynthetic Gene Clusters Guided by RNA-seq Data from Both <i>Streptomyces ansochromogenes</i> and ΔwblA.

Similar Datasets

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