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

Fukuda, Daisuke and Haines, Anthony S. and Song, Zhongshu and Murphy, Annabel C. and Hothersall, Joanne and Stephens, Elton R. and Gurney, Rachel and Cox, Russell J. and Crosby, John and Willis, Christine L. and Simpson, Thomas J. and Thomas, Christopher M. (2011) A Natural Plasmid Uniquely Encodes Two Biosynthetic Pathways Creating a Potent Anti-MRSA Antibiotic. PLoS ONE, 6 (3). e18031. ISSN 1932-6203

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URL of Published Version: http://dx.doi.org/10.1371/journal.pone.0018031

Identification Number/DOI: doi:10.1371/journal.pone.0018031

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.

Type of Work:Article
Date:31 March 2011 (Publication)
School/Faculty:Colleges (2008 onwards) > College of Life & Environmental Sciences
Department:School of Biosciences
Subjects:R Medicine (General)
QP Physiology
Institution:University of Birmingham
Copyright Holders:Public Library of Science
ID Code:801
Refereed:YES
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