Overproduction of Lactimidomycin by Cross-overexpression of Genes Encoding Streptomyces Antibiotic Regulatory Proteins

Overview

Journal Appl Microbiol Biotechnol

Specialties Biomedical Engineering
Biotechnology
Microbiology

Date 2015 Nov 11

PMID 26552797

Citations 8

Authors

Bo Zhang

Dong Yang

Yijun Yan

Guohui Pan

Wensheng Xiang

Ben Shen

Affiliations

Soon will be listed here.

Abstract

The glutarimide-containing polyketides represent a fascinating class of natural products that exhibit a multitude of biological activities. We have recently cloned and sequenced the biosynthetic gene clusters for three members of the glutarimide-containing polyketides-iso-migrastatin (iso-MGS) from Streptomyces platensis NRRL 18993, lactimidomycin (LTM) from Streptomyces amphibiosporus ATCC 53964, and cycloheximide (CHX) from Streptomyces sp. YIM56141. Comparative analysis of the three clusters identified mgsA and chxA, from the mgs and chx gene clusters, respectively, that were predicted to encode the PimR-like Streptomyces antibiotic regulatory proteins (SARPs) but failed to reveal any regulatory gene from the ltm gene cluster. Overexpression of mgsA or chxA in S. platensis NRRL 18993, Streptomyces sp. YIM56141 or SB11024, and a recombinant strain of Streptomyces coelicolor M145 carrying the intact mgs gene cluster has no significant effect on iso-MGS or CHX production, suggesting that MgsA or ChxA regulation may not be rate-limiting for iso-MGS and CHX production in these producers. In contrast, overexpression of mgsA or chxA in S. amphibiosporus ATCC 53964 resulted in a significant increase in LTM production, with LTM titer reaching 106 mg/L, which is five-fold higher than that of the wild-type strain. These results support MgsA and ChxA as members of the SARP family of positive regulators for the iso-MGS and CHX biosynthetic machinery and demonstrate the feasibility to improve glutarimide-containing polyketide production in Streptomyces strains by exploiting common regulators.

Citing Articles

Discrete Acyltransferases and Thioesterases in Iso-Migrastatin and Lactimidomycin Biosynthesis.

Steele A, Jiang H, Pan G, Lim S, Kalkreuter E, Kwong T Biochemistry. 2024; .

PMID: 38345531 PMC: 11623918. DOI: 10.1021/acs.biochem.3c00672.

A Review of the Microbial Production of Bioactive Natural Products and Biologics.

Pham J, Yilma M, Feliz A, Majid M, Maffetone N, Walker J Front Microbiol. 2019; 10:1404.

PMID: 31281299 PMC: 6596283. DOI: 10.3389/fmicb.2019.01404.

Dissolution of the Disparate: Co-ordinate Regulation in Antibiotic Biosynthesis.

McLean T, Wilkinson B, Hutchings M, Devine R Antibiotics (Basel). 2019; 8(2).

PMID: 31216724 PMC: 6627628. DOI: 10.3390/antibiotics8020083.

Challenges and opportunities for natural product discovery, production, and engineering in native producers versus heterologous hosts.

Teijaro C, Adhikari A, Shen B J Ind Microbiol Biotechnol. 2018; 46(3-4):433-444.

PMID: 30426283 PMC: 6405299. DOI: 10.1007/s10295-018-2094-5.

Regulation of antibiotic biosynthesis in actinomycetes: Perspectives and challenges.

Wei J, He L, Niu G Synth Syst Biotechnol. 2018; 3(4):229-235.

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