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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
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WRAP_J. Biol. Chem.-2017-Calvez-jbc.M116.764696.pdf - Accepted Version - Requires a PDF viewer. Download (9Mb) | Preview |
Official URL: http://doi.org/10.1074/jbc.M116.764696
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 | ||||||||||
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| Alternative Title: | |||||||||||
| Subjects: | Q Science > QR Microbiology > QR180 Immunology | ||||||||||
| Divisions: | Faculty of 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: |
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| Date of first compliant deposit: | 1 February 2017 | ||||||||||
| 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 | ||||||||||
| Funder: | France. Agence nationale de la recherche (ANR) | ||||||||||
| Grant number: | ORBiMP ANR-14-CE14-0003-01 | ||||||||||
| Open Access Version: |
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