A Natural Plasmid Uniquely Encodes Two Biosynthetic Pathways Creating a Potent Anti-MRSA Antibiotic

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

Research output: Contribution to journalArticle (Academic Journal)

41 Citations (Scopus)

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.

Original languageEnglish
Article numbere18031
Pages (from-to)-
Number of pages9
JournalPLoS ONE
Volume6
Issue number3
DOIs
Publication statusPublished - 31 Mar 2011

Projects

BIOSYNTHESIS OF POLYKETIDE ANTIBIOTIC MUPIROCIN BY PSEUDOMONAS FLUORESCENS

Simpson, T. J.

1/12/071/05/11

Project: Research

Cite this

Fukuda, D., Haines, A. S., Song, Z., Murphy, A. C., Hothersall, J., Stephens, E. R., Gurney, R., Cox, R. J., Crosby, J., Willis, C. L., Simpson, T. J., & Thomas, C. M. (2011). A Natural Plasmid Uniquely Encodes Two Biosynthetic Pathways Creating a Potent Anti-MRSA Antibiotic. PLoS ONE, 6(3), -. [e18031]. https://doi.org/10.1371/journal.pone.0018031