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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.

Author information

1
From the Institut de Biologie Structurale, Université Grenoble Alpes, CEA, CNRS, 38044 Grenoble, France.
2
the Department of Chemical Biology and Organic Chemistry, Institute of Biomembranes, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht 3584 CH, The Netherlands, and.
3
the School of Life Sciences, University of Warwick, Coventry CV4 7AL, United Kingdom.
4
From the Institut de Biologie Structurale, Université Grenoble Alpes, CEA, CNRS, 38044 Grenoble, France, andre.zapun@ibs.fr.

Abstract

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.

KEYWORDS:

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

PMID:
28062575
PMCID:
PMC5314180
DOI:
10.1074/jbc.M116.764696
[Indexed for MEDLINE]
Free PMC Article

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