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Mupirocin: biosynthesis, special features and applications of an antibiotic from a gram-negative bacterium

Rachel Gurney1, Christopher M Thomas

  • 1School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. Rsg893@bham.ac.uk

Applied Microbiology and Biotechnology
|February 22, 2011
PubMed

Insights

Mupirocin, an antibiotic targeting isoleucyl-tRNA synthetase, faces resistance due to a secondary enzyme. Modifying its biosynthetic pathway, inspired by marine bacteria, may overcome this challenge.

Area of Science:

  • Microbiology
  • Biochemistry
  • Genetics

Background:

  • Mupirocin is a polyketide antibiotic from Pseudomonas fluorescens.
  • Its biosynthesis involves a trans-AT type I polyketide synthase system with unique features like separate acyltransferase polypeptides and absent enoyl reductase domains.
  • Mupirocin inhibits isoleucyl-tRNA synthetase and is crucial for combating methicillin-resistant Staphylococcus aureus (MRSA).

Purpose of the Study:

  • To elucidate the complex biosynthetic pathway of mupirocin.
  • To understand the mechanisms of mupirocin resistance in Staphylococcus aureus.
  • To explore potential modifications of mupirocin to overcome existing resistance.

Main Methods:

  • Analysis of the mupirocin biosynthetic gene cluster.
  • Characterization of type I polyketide synthase components and their activities.
  • Investigation of the genetic basis for mupirocin resistance in Staphylococcus aureus.

Main Results:

  • The mupirocin biosynthetic pathway exhibits characteristics of the trans-AT group, including separate acyltransferase polypeptides and specific methyltransferase domains.
  • High-level mupirocin resistance in S. aureus is linked to a plasmid-encoded, eukaryotic-like isoleucyl-tRNA synthetase.
  • The absence of obvious loading mechanisms and enoyl reductase domains presents unique challenges in pathway elucidation.

Conclusions:

  • The unique biosynthetic pathway of mupirocin offers insights into polyketide synthesis.
  • Understanding mupirocin resistance mechanisms is critical for effective clinical use.
  • Investigating related pathways, such as that of thiomarinols, presents opportunities for developing next-generation mupirocin analogs to combat resistance.

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