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

Yue Li,Jine Li,Hua Xiang,Haiying Yu,Hanye Guan,Jihui Zhang,Jingjing Li,Huarong Tan

doi:10.3390/antibiotics10091097

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.

Highlights

Natural products from microbes play an important role in clinical treatments, animal husbandry and plant crop protection [1,2]
In order to obtain a complete genome sequence of S. ansochromogenes 7100, the third generation sequencing was performed on a PacBio RSII platform
The genome of S. ansochromogenes 7100 is a linear chromosome with a repetitive sequence content of 2.37% (Table S3), which is composed of 8235 protein-coding genes (Table S4), 72 tRNAs, 18 rRNA and 50 nc RNAs genes (Table S5)

Summary

Introduction

Natural products from microbes play an important role in clinical treatments, animal husbandry and plant crop protection [1,2]. Streptomycetes have the potential to produce more new natural products than those previously recognized under laboratory conditions. With the rapid development of genome sequencing technology and analysis tools, more and more cryptic secondary metabolites have been mined and the activated cryptic gene clusters have been identified through various strategies, which provide more opportunities to discover new natural products or drug candidates [3,4]. Used or proposed methods for activating the ‘cryptic’ pathways include the optimization of culture and fermentation conditions, heterologous expression, genetic manipulations of regulatory genes or gene clusters, omic studies, co-culture of different microbes, induction of signaling molecules, ribosomal engineering, reporter-guided strategy, and so on [5,6,7]. Microbial natural product databases, such as ’The Natural Products Atlas’ (https://www.npatlas.org/, accessed on 9 September 2021), antiSMASH database (https://antismash.secondarymetabolites.org, accessed on 9 September 2021), and CH-NMR-NP database

Methods

Results

Conclusion