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Error-prone initiation factor 2 mutations reduce the fitness cost of antibiotic resistance
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Dan Andersson)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. (Måns Ehrenberg)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Dan Andersson)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. (Måns Ehrenberg)
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2010 (English)In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, ISSN 20132454, Vol. 75, no 5, p. 1299-1313Article in journal (Refereed) Published
Abstract [en]

Mutations in the fmt gene (encoding formyl methionine transferase) that eliminate formylation of initiator tRNA (Met-tRNA(i)) confer resistance to the novel antibiotic class of peptide deformylase inhibitors (PDFIs) while concomitantly reducing bacterial fitness. Here we show in Salmonella typhimurium that novel mutations in initiation factor 2 (IF2) located outside the initiator tRNA binding domain can partly restore fitness of fmt mutants without loss of antibiotic resistance. Analysis of initiation of protein synthesis in vitro showed that with non-formylated Met-tRNA(i) IF2 mutants initiated much faster than wild-type IF2, whereas with formylated fMet-tRNA(i) the initiation rates were similar. Moreover, the increase in initiation rates with Met-tRNA(i) conferred by IF2 mutations in vitro correlated well with the increase in growth rate conferred by the same mutations in vivo, suggesting that the mutations in IF2 compensate formylation deficiency by increasing the rate of in vivo initiation with Met-tRNA(i). IF2 mutants had also a high propensity for erroneous initiation with elongator tRNAs in vitro, which could account for their reduced fitness in vivo in a formylation-proficient strain. More generally, our results suggest that bacterial protein synthesis is mRNA-limited and that compensatory mutations in IF2 could increase the persistence of PDFI-resistant bacteria in clinical settings.

Place, publisher, year, edition, pages
Wiley-Blackwell , 2010. Vol. 75, no 5, p. 1299-1313
National Category
Microbiology in the medical area
Research subject
Microbiology
Identifiers
URN: urn:nbn:se:uu:diva-121733DOI: 10.1111/j.1365-2958.2010.07057.xISI: 000274808800020OAI: oai:DiVA.org:uu-121733DiVA, id: diva2:306256
Available from: 2010-04-26 Created: 2010-03-29 Last updated: 2018-01-12Bibliographically approved

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Publisher's full texthttp://www3.interscience.wiley.com/journal/123271654/abstract

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Zorzet, AnnaAndersson, Dan I

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