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Substitutions in PBP2b from β-lactam resistant Streptococcus pneumoniae have different effects on enzymatic activity and drug reactivity

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Calvez, Philippe, Breukink, Eefjan, Roper, David I., Dib, Mélanie, Contreras-Martel, Carlos and Zapun, André (2017) Substitutions in PBP2b from β-lactam resistant Streptococcus pneumoniae have different effects on enzymatic activity and drug reactivity. Journal of Biological Chemistry, 292 (7). pp. 2854-2865. doi:10.1074/jbc.M116.764696 ISSN 0021-9258.

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Official URL: http://doi.org/10.1074/jbc.M116.764696

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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, as 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.

Item Type: Journal Article
Alternative Title:
Subjects: Q Science > QR Microbiology > QR180 Immunology
Divisions: Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Drug resistance in microorganisms , Biochemistry, Peptidoglycans, Streptococcus, Enzyme kinetics
Journal or Publication Title: Journal of Biological Chemistry
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Official Date: 17 February 2017
Dates:
DateEvent
17 February 2017Published
6 January 2017Available
6 January 2017Accepted
25 October 2016Submitted
Volume: 292
Number: 7
Page Range: pp. 2854-2865
DOI: 10.1074/jbc.M116.764696
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access
Date of first compliant deposit: 1 February 2017
Date of first compliant Open Access: 2 February 2017
Funder: France. Agence nationale de la recherche (ANR)
Grant number: ORBiMP ANR-14-CE14-0003-01
Open Access Version:
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