AAC Accepts, published online ahead of print on 26 October 2009

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00699-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A Single Mutation in the Enzyme I of the Sugar Phosphotransferase System Confers Penicillin Tolerance to Streptococcus gordonii

A. Bizzini^*, J. M. Entenza, O. Michielin, I. Arnold, B. Erni, and P. Moreillon

Department of Fundamental Microbiology, Faculty of Biology and Medicine, Biophore Building, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1066 Epalinges, Switzerland; Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012, Bern, Switzerland

^* To whom correspondence should be addressed. Email: Alain.Bizzini{at}unil.ch.

Tolerance is a poorly understood phenomenon allowing bacteria exposed to a bactericidal antibiotic to stop their growth and withstand drug-induced killing. This survival ability has been implicated in antibiotic treatment failures. Here, we describe a single nucleotide mutation (tol1) in a tolerant Streptococcus gordonii strain (Tol1) that is sufficient to provide tolerance in vitro and in vivo. It induces a proline to arginine substitution (P483R) in the homodimerization interface of the Enzyme I of the sugar phosphotransferase system, resulting in a diminished sugar uptake. In vitro, the susceptible wild-type (WT) and Tol1 cultures lost 4.5 and 0.6 log₁₀CFU/ml, respectively, after 24 h of penicillin exposure. Introduction of tol1 in WT (WT P483R) conferred tolerance (loss of 0.7 log₁₀CFU/ml/24h), whereas restitution of the parent sequence in Tol1 (Tol1 R483P) restored antibiotic susceptibility. Moreover, penicillin treatment of experimental endocarditis showed a complete inversion in outcome, with a failure of therapy in rats infected with WT P483R and a complete disappearance of bacteria in animals infected with Tol1 R483P.