Article: article from journal or magazin.
A single mutation in enzyme I of the sugar phosphotransferase system confers penicillin tolerance to Streptococcus gordonii.
Antimicrobial Agents and Chemotherapy
Tolerance is a poorly understood phenomenon that allows 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 enzyme I of the sugar phosphotransferase system, resulting in diminished sugar uptake. In vitro, the susceptible wild-type (WT) and Tol1 cultures lost 4.5 and 0.6 log(10) CFU/ml, respectively, after 24 h of penicillin exposure. The introduction of tol1 into the WT (WT P483R) conferred tolerance (a loss of 0.7 log(10) CFU/ml/24 h), whereas restitution of the parent sequence in Tol1 (Tol1 R483P) restored antibiotic susceptibility. Moreover, penicillin treatment of rats in an experimental model of endocarditis showed a complete inversion in the outcome, with a failure of therapy in rats infected with WT P483R and the complete disappearance of bacteria in animals infected with Tol1 R483P.
Amino Acid Substitution, Anti-Bacterial Agents/pharmacology, Carbohydrate Metabolism/drug effects, Chromosome Mapping, Cloning, Molecular, DNA, Bacterial/genetics, Dimerization, Endocarditis/microbiology, Energy Metabolism/genetics, Energy Metabolism/physiology, Gene Deletion, Genetic Linkage/genetics, Glucose/metabolism, Microbial Sensitivity Tests, Models, Molecular, Penicillin Resistance/genetics, Penicillins/pharmacology, Phosphoenolpyruvate Sugar Phosphotransferase System/genetics, Point Mutation/physiology, Protein Conformation, Streptococcus gordonii/drug effects, Streptococcus gordonii/genetics, Transformation, Genetic
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