A natural plasmid uniquely encodes two biosynthetic pathways creating a potent anti-MRSA antibiotic

verfasst von

Daisuke Fukuda, Anthony S. Haines, Zhongshu Song, Annabel C. Murphy, Joanne Hothersall, Elton R. Stephens, Rachel Gurney, Russell J. Cox, John Crosby, Christine L. Willis, Thomas J. Simpson, Christopher M. Thomas

Abstract

Background: Understanding how complex antibiotics are synthesised by their producer bacteria is essential for creation of new families of bioactive compounds. Thiomarinols, produced by marine bacteria belonging to the genus Pseudoalteromonas, are hybrids of two independently active species: the pseudomonic acid mixture, mupirocin, which is used clinically against MRSA, and the pyrrothine core of holomycin. Methodology/Principal Findings: High throughput DNA sequencing of the complete genome of the producer bacterium revealed a novel 97 kb plasmid, pTML1, consisting almost entirely of two distinct gene clusters. Targeted gene knockouts confirmed the role of these clusters in biosynthesis of the two separate components, pseudomonic acid and the pyrrothine, and identified a putative amide synthetase that joins them together. Feeding mupirocin to a mutant unable to make the endogenous pseudomonic acid created a novel hybrid with the pyrrothine via "mutasynthesis" that allows inhibition of mupirocin-resistant isoleucyl-tRNA synthetase, the mupirocin target. A mutant defective in pyrrothine biosynthesis was also able to incorporate alternative amine substrates. Conclusions/Significance: Plasmid pTML1 provides a paradigm for combining independent antibiotic biosynthetic pathways or using mutasynthesis to develop a new family of hybrid derivatives that may extend the effective use of mupirocin against MRSA.

Externe Organisation(en)

University of Birmingham
University of Bristol

Typ

Artikel

Journal

PLOS ONE

Band

6

ISSN

1932-6203

Publikationsdatum

07.04.2011

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Biochemie, Genetik und Molekularbiologie (insg.), Agrar- und Biowissenschaften (insg.), Allgemein

Ziele für nachhaltige Entwicklung

SDG 14 – Lebensraum Wasser

Elektronische Version(en)

https://doi.org/10.1371/journal.pone.0018031 (Zugang: Offen)