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Mutasynthesis and Antibiotic Activity of Mupirocin Analogues
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DOI：10.1002/cbic.70439.png)
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Abstract
En 中文
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.
Keywords:
antimicrobial
Bacillus subtilis
biosynthesis
metabolic engineering
mupirocin
polyketide
Pseudomonas fluorescens
synthesis
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