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Published on: January 2, 2014
Resistance to and synthesis of the antibiotic mupirocin
Christopher M Thomas1, Joanne Hothersall, Christine L Willis
1School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Abstract:
Mupirocin, a polyketide antibiotic produced by Pseudomonas fluorescens, is used to control the carriage of methicillin-resistant Staphylococcus aureus on skin and in nasal passages as well as for various skin infections. Low-level resistance to the antibiotic arises by mutation of the mupirocin target, isoleucyl-tRNA synthetase, whereas high-level resistance is due to the presence of an isoleucyl-tRNA synthetase with many similarities to eukaryotic enzymes. Mupirocin biosynthesis is carried out by a combination of type I multifunctional polyketide synthases and tailoring enzymes encoded in a 75 kb gene cluster. Chemical synthesis has also been achieved. This knowledge should allow the synthesis of new and modified antibiotics for the future.
Insights
Mupirocin, an antibiotic for skin infections and MRSA, exhibits resistance through target mutation or alternative enzymes. Understanding its biosynthesis and chemical synthesis aids in developing future antibiotics.
Area of Science:
- Microbiology
- Biochemistry
- Medicinal Chemistry
Background:
- Mupirocin is a polyketide antibiotic effective against methicillin-resistant Staphylococcus aureus (MRSA) and various skin infections.
- Resistance to mupirocin can be low-level (target mutation) or high-level (alternative isoleucyl-tRNA synthetase).
Purpose of the Study:
- To summarize the mechanisms of mupirocin resistance.
- To describe the biosynthesis of mupirocin.
- To highlight the potential for future antibiotic development.
Main Methods:
- Review of existing literature on mupirocin.
- Analysis of mupirocin biosynthesis pathways.
- Consideration of chemical synthesis approaches.
Main Results:
- Identified two distinct mechanisms of mupirocin resistance.
- Detailed the genetic basis of mupirocin biosynthesis involving polyketide synthases and tailoring enzymes.
- Confirmed the feasibility of chemical synthesis for mupirocin.
Conclusions:
- Knowledge of mupirocin's resistance mechanisms and biosynthesis is crucial for combating MRSA.
- The biosynthesis pathway and chemical synthesis provide a foundation for creating novel mupirocin derivatives and antibiotics.
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