Selected Mutations Reveal New Intermediates in the Biosynthesis of Mupirocin and the Thiomarinol Antibiotics. (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. Volume 129:Number 14(2017)
• Page Start: 3988
• Page End: 3992
• Publication Date: 2017-02-09
• Subjects: Antibiotika -- Biosynthese -- Mutasynthese -- Polyketide -- Strukturaufklärung; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201611590
• Languages: English
• ISSNs: 0044-8249

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.