Selected Mutations Reveal New Intermediates in the Biosynthesis of Mupirocin and the Thiomarinol Antibiotics.
Angew Chem Int Ed Engl
; 56(14): 3930-3934, 2017 03 27.
Article
in En
| MEDLINE
| ID: mdl-28181382
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 mupirocinâ
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 C6â
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Mupirocin
/
Polyketide Synthases
/
Methicillin-Resistant Staphylococcus aureus
/
Anti-Bacterial Agents
Language:
En
Journal:
Angew Chem Int Ed Engl
Year:
2017
Type:
Article
Affiliation country:
United kingdom