Selected Mutations Reveal New Intermediates in the Biosynthesis of Mupirocin and the Thiomarinol Antibiotics. Issue 14 (9th February 2017)

• Record Type: Journal Article
• Authors: Gao, Shu‐Shan; Wang, Luoyi; Song, Zhongshu; Hothersall, Joanne; Stevens, Elton R.; Connolly, Jack; Winn, Peter J.; Cox, Russell J.; Crump, Matthew P.; Race, Paul R.; Thomas, Christopher M.; Simpson, Thomas J.; Willis, Christine L.
• Is Part Of: Angewandte Chemie international edition. Volume 56:Issue 14(2017)
• Page Start: 3930
• Page End: 3934
• Publication Date: 2017-02-09
• Subjects: antibiotics -- biosynthesis -- mutasynthesis -- polyketides -- structure determination; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201611590
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Thiomarinol and mupirocin are assembled on similar polyketide/fatty acid backbones and exhibit potent antibiotic activity against methicillin‐resistant Staphylococcus aureus (MRSA). They both contain a tetrasubstituted tetrahydropyran (THP) ring that is essential for biological activity. Mupirocin is a mixture of pseudomonic acids (PAs). Isolation of the novel compound mupirocin P, which contains a 7‐hydroxy‐6‐keto‐substituted THP, from a ΔmupP strain and chemical complementation experiments confirm that the first step in the conversion of PA‐B into the major product PA‐A is oxidation at the C6 position. In addition, nine novel thiomarinol (TM) derivatives with different oxidation patterns decorating the central THP core were isolated after gene deletion ( tmlF ). These metabolites are in accord with the THP ring formation and elaboration in thiomarinol following a similar order to that found in mupirocin biosynthesis, despite the lack of some of the equivalent genes. Novel mupirocin–thiomarinol hybrids were also synthesized by mutasynthesis. Abstract : A long and winding road : Novel metabolites from mutant strains of P. fluorescens and the marine bacterium Pseudoalteromonas were isolated and structurally characterized. In combination with complementation experiments, it was shown that formation of the tetrahydropyran ring and elaboration of thiomarinol follow a similar order to that in mupirocin biosynthesis despite the lack of some genes.