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J Biol Chem. 2017 Feb 17;292(7):2854-2865. doi: 10.1074/jbc.M116.764696. Epub 2017 Jan 6.

Substitutions in PBP2b from β-Lactam-resistant Streptococcus pneumoniae Have Different Effects on Enzymatic Activity and Drug Reactivity.

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From the Institut de Biologie Structurale, Université Grenoble Alpes, CEA, CNRS, 38044 Grenoble, France.
the Department of Chemical Biology and Organic Chemistry, Institute of Biomembranes, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht 3584 CH, The Netherlands, and.
the School of Life Sciences, University of Warwick, Coventry CV4 7AL, United Kingdom.
From the Institut de Biologie Structurale, Université Grenoble Alpes, CEA, CNRS, 38044 Grenoble, France,


Pneumococcus resists β-lactams by expressing variants of its target enzymes, the penicillin-binding proteins (PBPs), with many amino acid substitutions. Up to 10% of the sequence can be modified. These altered PBPs have a much reduced reactivity with the drugs but retain their physiological activity of cross-linking the peptidoglycan, the major constituent of the bacterial cell wall. However, because β-lactams are chemical and structural mimics of the natural substrate, resistance mediated by altered PBPs raises the following paradox: how PBPs that react poorly with the drugs maintain a sufficient level of activity with the physiological substrate. This question is addressed for the first time in this study, which compares the peptidoglycan cross-linking activity of PBP2b from susceptible and resistant strains with their inhibition by different β-lactams. Unexpectedly, the enzymatic activity of the variants did not correlate with their antibiotic reactivity. This finding indicates that some of the numerous amino acid substitutions were selected to restore a viable level of enzymatic activity by a compensatory molecular mechanism.


Streptococcus; antibiotic resistance; cell wall; enzyme kinetics; peptidoglycan

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