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- Title
Selected Mutations Reveal New Intermediates in the Biosynthesis of Mupirocin and the Thiomarinol Antibiotics.
- Authors
Gao, Shu-Shan; Wang, Luoyi; Song, Zhongshu; Crump, Matthew P.; Simpson, Thomas J.; Willis, Christine L.; Cox, Russell J.; Hothersall, Joanne; Stevens, Elton R.; Connolly, Jack; Winn, Peter J.; Thomas, Christopher M.; Race, Paul R.
- 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.
- Subjects
GENETIC mutation; BIOSYNTHESIS; MUPIROCIN; ANTIBIOTICS; FATTY acids
- Publication
Angewandte Chemie International Edition, 2017, Vol 56, Issue 14, p3930
- ISSN
1433-7851
- Publication type
Article
- DOI
10.1002/anie.201611590