Details
| Original language | English |
|---|---|
| Pages (from-to) | 3930-3934 |
| Number of pages | 5 |
| Journal | Angewandte Chemie |
| Volume | 56 |
| Issue number | 14 |
| Publication status | Published - 27 Mar 2017 |
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.
Keywords
- antibiotics, biosynthesis, mutasynthesis, polyketides, structure determination
ASJC Scopus subject areas
- Chemical Engineering(all)
- Catalysis
- Chemistry(all)
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In: Angewandte Chemie , Vol. 56, No. 14, 27.03.2017, p. 3930-3934.
Research output: Contribution to journal › Article › Research › peer review
}
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 -