TY - JOUR

T1 - Selected Mutations Reveal New Intermediates in the Biosynthesis of Mupirocin and the Thiomarinol Antibiotics

AU - Gao, Shu Shan

AU - Wang, Luoyi

AU - Song, Zhongshu

AU - Hothersall, Joanne

AU - Stevens, Elton R.

AU - Connolly, Jack

AU - Winn, Peter J.

AU - Cox, Russell J.

AU - Crump, Matthew P.

AU - Race, Paul R.

AU - Thomas, Christopher M.

AU - Simpson, Thomas J.

AU - Willis, Christine L.

N1 - Funding information: This work was funded by the BBSRC and EPSRC including through BrisSynBio, the Bristol Centre for Synthetic Biology (BB/L01386X/1), awards BB/I014039/1, BB/I014373/1, and a BBSRC DTP studentship (BB/J014532/1). We thank the EPSRC (EP/F066104/1) for LCMS equipment.

PY - 2017/3/27

Y1 - 2017/3/27

N2 - 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.

AB - 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.

KW - antibiotics

KW - biosynthesis

KW - mutasynthesis

KW - polyketides

KW - structure determination

UR - http://www.scopus.com/inward/record.url?scp=85011973235&partnerID=8YFLogxK

U2 - 10.1002/anie.201611590

DO - 10.1002/anie.201611590

M3 - Article

C2 - 28181382

AN - SCOPUS:85011973235

VL - 56

SP - 3930

EP - 3934

JO - Angewandte Chemie

JF - Angewandte Chemie

SN - 1433-7851

IS - 14

ER -