Mechanism of β-lactam action in Streptococcus pneumoniae: the piperacillin paradox.
The human pathogen Streptococcus pneumoniae has been treated for decades with β-lactam antibiotics. Its resistance is now widespread, mediated by the expression of mosaic variants of the target enzymes, the penicillin-binding proteins (PBPs). Understanding the mode of action of β-lactams, not only in molecular detail but also in their physiological consequences, will be crucial to improving these drugs and any counterresistances. 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 monofunctional transpeptidases involved in peptidoglycan assembly. PBP2x participates in septal synthesis, while PBP2b functions in peripheral elongation. The formation of the "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, the localization of the PBPs by epifluorescence microscopy, and the determination of the inhibition time course of the different PBPs, we propose a model of peptidoglycan assembly that accounts for the piperacillin paradox.
Université Grenoble Alpes, IBS, Grenoble, France CNRS, IBS, Grenoble, France CEA, IBS, Grenoble, France.
Jules
J
Philippe
Université Grenoble Alpes, IBS, Grenoble, France CNRS, IBS, Grenoble, France CEA, IBS, Grenoble, France.
Benoit
B
Gallet
Université Grenoble Alpes, IBS, Grenoble, France CNRS, IBS, Grenoble, France CEA, IBS, Grenoble, France.
Cécile
C
Morlot
Department of Microbiology, University of Kaiserslautern, Kaiserslautern, Germany.
Dalia
D
Denapaite
Department of Microbiology, University of Kaiserslautern, Kaiserslautern, Germany Alfried Krupp Wissenschaftskolleg, Greifswald, Germany.
Regine
R
Hakenbeck
University of Science and Technology of China, Hefei, China.
Yuxin
Y
Chen
Université Grenoble Alpes, IBS, Grenoble, France CNRS, IBS, Grenoble, France CEA, IBS, Grenoble, France.
Thierry
T
Vernet
Université Grenoble Alpes, IBS, Grenoble, France CNRS, IBS, Grenoble, France CEA, IBS, Grenoble, France andre.zapun@ibs.fr.
André
A
Zapun
D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D058990:Molecular Targeted Therapy; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010878:Piperacillin / Q000494:pharmacology*; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D018440:beta-Lactam Resistance / Q000187:drug effects
D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D046915:Penicillin-Binding Proteins; C072223:PBP 2x protein, Streptococcus; D019881:Aminoacyltransferases; C478701:penicillin-binding protein 2b, Streptococcus; D010878:Piperacillin