Authors
Sarah M Husain, Luoyi Wang, Li-Chen Han, James I Bowen, Zhongshu Song, Felix de Courcy-Ireland, Ashley J Winter, Thomas J Simpson, Paul R Race, James Spencer, Matthew P Crump, Christine L Willis
Published in
Chembiochem : a European journal of chemical biology. Volume 27. Issue 13. Pages e70439. Jul 14, 2026.
Abstract
With growing understanding of complex biosynthetic pathways to natural products, mutasynthesis, which combines metabolic engineering with chemical synthesis, is becoming an increasingly important tool to produce novel compounds. Mupirocin, isolated from Pseudomonas fluorescens, is a mixture of pseudomonic acids (PAs) that exhibit antibiotic activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus. We have developed a flexible approach, based on mutasynthesis, for the preparation of a library of novel PA analogues. The antimicrobial activities of the natural products and synthetic analogues were evaluated against Bacillus subtilis and four Staphylococcus aureus strains. Interestingly, one of the analogues retained antimicrobial activity in all the assays but lacked structural features that render PA-A unstable, that is, the 10,11-epoxide (replaced by an alkene) and ester linkage (replaced by a ketone). In addition, mutasynthesis allowed the preparation of an analogue of a key biosynthetic intermediate (desepoxy-PA-B) in which the C9 hydroxy fatty acid is replaced by a C7 analogue. Feeding studies with mutant strains of Pseudomonas fluorescens revealed that C7-desepoxy-PA-B was converted to the novel metabolite C7-PA-C with loss of the 8-hydroxyl group but with no extension to the C9 side chain.
PMID:
42376734
Bibliographic data and abstract were imported from PubMed on 30 Jun 2026.
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