Antimicrob Agents Chemother. 2014 Nov 10. pii: AAC.04283-14. [Epub ahead of print]
Mechanism of β-Lactam Action in Streptococcus pneumoniae: the Piperacillin Paradox.
Philippe J1, Gallet B1, Morlot C1, Denapaite D2, Hakenbeck R3, Chen Y4, Vernet T1, Zapun A5.
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Abstract
The human pathogen Streptococcus pneumoniae has been fought for decades with β-lactam antibiotics. Resistance is now widespread, mediated by the expression of mosaic variants of the target enzymes, the penicillin-binding proteins or PBPs. Understanding the mode of action of β-lactams, not only in molecular details, but also in their physiological consequences, will be crucial to improve these drugs and counter resistance. In this work, we investigate the piperacillin paradox, by which this β-lactam selects primarily variants of PBP2b, whereas its most reactive target is PBP2x. These PBPs are both essential mono-functional transpeptidases involved in peptidoglycan assembly. PBP2x participates to septal synthesis, while PBP2b functions in peripheral elongation. The formation of "lemon"-shaped cells induced by piperacillin treatment is consistent with the inhibition of PBP2x. Following the examination of treated and untreated cells by electron microscopy, localization of the PBPs by epifluorescence microscopy, and determination of the inhibition time-course of the different PBPs, we propose a model of peptidoglycan assembly that can account for the piperacillin paradox.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.
PMID: 25385114 [PubMed - as supplied by publisher]
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