Resistance to and synthesis of the antibiotic mupirocin

Key Points The spread of methicillin-resistant Staphylococcus aureus (MRSA) necessitates the development of new antibiotics. The control of mupirocin production in soil bacteria is in proportion to bacterial cell density. Mupirocin inhibits isoleucyl-tRNA synthetase, and spontaneous mupirocin-resistant mutants are generally less fit than wild-type bacteria. Mupirocin can be used topically but not systemically owing to its rapid hydrolysis. Mupirocin is made by a complex polyketide biosynthetic pathway. 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. Mupirocin is a polyketide antibiotic produced by Pseudomonas fluorescens that is used to control the carriage of methicillin-resistant Staphylococcus aureus . Here, Thomas and colleagues describe the mechanisms underlying the mode of action and biosynthesis of mupirocin and discuss how this understanding could lead to the development of novel antibiotics. 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.