Selected Mutations Reveal New Intermediates in the Biosynthesis of Mupirocin and the Thiomarinol Antibiotics.
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.
School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK.
Shu-Shan
SS
Gao
School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK.
Luoyi
L
Wang
School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK.
Zhongshu
Z
Song
School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
Joanne
J
Hothersall
School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
Elton R
ER
Stevens
School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
Jack
J
Connolly
School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
Peter J
PJ
Winn
School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK.|BMWZ, Leibniz-Universität Hannover, Schneiderberg 38, 30167, Hannover, Germany.
Russell J
RJ
Cox
School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK.
Matthew P
0000-0002-7868-5818
MP
Crump
School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK.
Paul R
0000-0003-0184-5630
PR
Race
School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
Christopher M
CM
Thomas
School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK.
Thomas J
0000-0003-0777-1935
TJ
Simpson
School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK.
Christine L
0000-0002-3919-3642
CL
Willis
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D016712:Mupirocin / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology*; D009154:Mutation; D048630:Polyketide Synthases / Q000235:genetics* / Q000378:metabolism
D000900:Anti-Bacterial Agents; C085617:thiomarinol; D048630:Polyketide Synthases; D016712:Mupirocin
antibiotics; biosynthesis; mutasynthesis; polyketides; structure determination