1887

Abstract

Mupirocin (pseudomonic acid) is a polyketide antibiotic, targeting isoleucyl-tRNA synthase, and produced by NCIMB 10586. It is used clinically as a topical treatment for staphylococcal infections, particularly in contexts where there is a problem with methicillin-resistant (MRSA). In studying the mupirocin biosynthetic cluster the authors identified two putative regulatory genes, and , whose predicted amino acid sequences showed significant identity to proteins involved in quorum-sensing-dependent regulatory systems such as LasR/LuxR (transcriptional activators) and LasI/LuxI (synthases for acylhomoserine lactones – AHLs – that activate LasR/LuxR). Inactivation by deletion mutations using a suicide vector strategy confirmed the requirement for both genes in mupirocin biosynthesis. Cross-feeding experiments between bacterial strains as well as solvent extraction showed that, as predicted, wild-type NCIMB 10586 produces a diffusible substance that overcomes the defect of a mutant. Use of biosensor strains showed that the MupI product can activate the system and that produces one or more compounds that can replace the MupI product. Insertion of a reporter gene into , the first ORF of the mupirocin biosynthetic operon, showed that together / control expression of the operon in such a way that the cluster is switched on late in exponential phase and in stationary phase.

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2001-08-01
2020-03-28
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