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Mutasynthesis and Antibiotic Activity of Mupirocin Analogues

Sarah M Husain1,2, Luoyi Wang1,3, Li-Chen Han1

  • 1School of Chemistry, Cantock's Close, University of Bristol, Bristol, UK.

Chembiochem : a European Journal of Chemical Biology
|June 30, 2026
PubMed

Insights

Mutasynthesis enabled the creation of novel pseudomonic acid (PA) analogues with retained antibiotic activity. One analogue, lacking unstable features, shows promise for developing new antibacterial agents against resistant bacteria.

Area of Science:

  • Natural Product Biosynthesis
  • Synthetic Biology
  • Medicinal Chemistry

Background:

  • Mupirocin, a mixture of pseudomonic acids (PAs), possesses antibiotic properties against Gram-positive bacteria, including MRSA.
  • Understanding complex biosynthetic pathways is crucial for developing novel antimicrobial compounds.
  • Mutasynthesis, combining metabolic engineering and chemical synthesis, offers a powerful strategy for generating compound diversity.

Purpose of the Study:

  • To develop a flexible mutasynthesis approach for creating novel pseudomonic acid analogues.
  • To evaluate the antimicrobial activities of these synthetic analogues.
  • To investigate the structure-activity relationships of PAs.

Main Methods:

  • Utilized mutasynthesis to generate a library of novel PA analogues.
  • Assessed antimicrobial activity against Bacillus subtilis and four Staphylococcus aureus strains.
  • Synthesized a C7 analogue of a key biosynthetic intermediate (desepoxy-PA-B) and conducted feeding studies.

Main Results:

  • One novel PA analogue retained significant antimicrobial activity while lacking the 10,11-epoxide and ester linkage found in PA-A.
  • This analogue demonstrated stability by replacing the epoxide with an alkene and the ester with a ketone.
  • Feeding studies confirmed the conversion of C7-desepoxy-PA-B to a novel metabolite, C7-PA-C, with modifications at the 8-hydroxyl group and side chain.

Conclusions:

  • Mutasynthesis is an effective strategy for producing stable and active pseudomonic acid analogues.
  • The developed analogues show potential as new antibacterial agents, particularly against resistant strains.
  • Further research into these stable analogues could lead to the development of improved antibiotics.
Keywords:
Bacillus subtilisPseudomonas fluorescensantimicrobialbiosynthesismetabolic engineeringmupirocinpolyketidesynthesis

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