Mupirocin: biosynthesis, special features and applications of an antibiotic from a Gram-negative bacterium

Mupirocin is a polyketide antibiotic produced by Pseudomonas fluorescens. The biosynthetic cluster encodes 6 type I polyketide synthase multifunctional proteins and 29 single function proteins. The biosynthetic pathway belongs to the trans-AT group in which acyltransferase activity is provided by a separate polypeptide rather than in-cis as found in the original type I polyketide synthases. Special features of this group are in-cis methyltransferase domains and a trans-acting HMG-CoA synthase-cassette which insert alpha- and beta- methyl groups respectively while enoyl reductase domains are absent from the condensing modules. In addition, for the mupirocin system, there is no obvious loading mechanism for initiation of the polyketide chain and many aspects of the pathway remain to be elucidated. Mupirocin inhibits isoleucyl-tRNA synthetase and has been used since 1985 to help prevent infection by methicillin-resistant Staphylococcus aureus, particularly within hospitals. Resistance to mupirocin was first detected in 1987 and high-level resistance in S. aureus is due to a plasmid-encoded second isoleucyl-tRNA synthetase, a more eukaryotic-like enzyme. Recent analysis of the biosynthetic pathway for thiomarinols from marine bacteria opens up possibilities to modify mupirocin so as to overcome this resistance.