Key Points
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The spread of methicillin-resistant Staphylococcus aureus (MRSA) necessitates the development of new antibiotics.
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The control of mupirocin production in soil bacteria is in proportion to bacterial cell density.
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Mupirocin inhibits isoleucyl-tRNA synthetase, and spontaneous mupirocin-resistant mutants are generally less fit than wild-type bacteria.
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Mupirocin can be used topically but not systemically owing to its rapid hydrolysis.
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Mupirocin is made by a complex polyketide biosynthetic pathway.
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Engineering mupirocin production in vivo or producing it by chemical synthesis could enable the production of new derivatives, the biological activity of which could then be explored.
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.
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Acknowledgements
Current work on mupirocin in the authors' laboratories is supported by grant BB/E021611/1, which is jointly funded by the Biotechnology and Biological Sciences Research Council and the Engineering and Physical Sciences Research Council.
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DATABASES
Entrez Genome Project
Methanothermobacter thermautotrophicus
Salmonella enterica subsp. enterica serovar Typhimurium
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Glossary
- Isoleucyl-tRNA synthetase
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The enzyme responsible for the addition of isoleucine to tRNAIle, using the energy from ATP to drive the reaction.
- Rossman fold
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A structural motif found in proteins that bind nucleotides. It is composed of three or more parallel β-strands linked to and alternating with two α-helices.
- Stringent response
-
A reaction to amino acid starvation that is found in all prokaryotes and that prevents the wasteful biosynthesis of gene expression machinery. Guanosine pentaphosphate and guanosine tetraphosphate are produced by the ribosomal proteins GTP pyrophosphokinase (RelA) and L11A when there are no charged tRNAs available to bind to the ribosome, and this is converted to a signal that reduces the synthesis of ribosomal and RNA polymerase components.
- Methicillin-resistant S. aureus
-
Specific strains of S. aureus that have acquired a mutation in penicillin-binding protein 2 (PBP2), rendering them resistant to methicillin, along with having resistance to many other β-lactam antibiotics and other commonly used antibiotics owing to gene transfer from plasmids and transposable elements.
- Polyketide
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A compound that is synthesized by the successive decarboxylative condensation of extender units such as malonate and methylmalonate onto organic acid starter units such as acetate to formally create a polymer with keto groups on alternate backbone carbons.
- Polyketide synthase
-
An enzyme that is responsible for polyketide synthesis and has, at a minimum, ketosynthase and acyl carrier protein functions that carry the starter and extender units, respectively. Type I polyketide synthases incorporate these functions into a single polypeptide and have one ketosynthase and one acyl carrier protein for each condensation, whereas type II enzymes consist of multiple unifunctional polypeptides that catalyse multiple rounds of condensation.
- Quorum sensing
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A mechanism of regulating gene expression in response to cell density per unit volume, normally involving a diffusible signal that is produced constitutively by the cells and to which the cells respond when the concentration rises above a certain threshold.
- Ene-ISMS reaction
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A reaction involving an unsaturated double carbon bond followed by a concomitant intramolecular silyl-mediated Sakurai (ISMS) cyclization.
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Thomas, C., Hothersall, J., Willis, C. et al. Resistance to and synthesis of the antibiotic mupirocin. Nat Rev Microbiol 8, 281–289 (2010). https://doi.org/10.1038/nrmicro2278
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DOI: https://doi.org/10.1038/nrmicro2278
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