Mechanism of β-lactam action in Streptococcus pneumoniae: the piperacillin paradox

Antimicrob Agents Chemother. 2015 Jan;59(1):609-21. doi: 10.1128/AAC.04283-14. Epub 2014 Nov 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoacyltransferases / antagonists & inhibitors
  • Aminoacyltransferases / genetics
  • Aminoacyltransferases / metabolism
  • Bacterial Proteins / metabolism
  • Cytoskeletal Proteins / metabolism
  • Microbial Sensitivity Tests
  • Molecular Targeted Therapy
  • Penicillin-Binding Proteins / antagonists & inhibitors*
  • Penicillin-Binding Proteins / genetics
  • Penicillin-Binding Proteins / metabolism
  • Piperacillin / pharmacology*
  • Streptococcus pneumoniae / drug effects*
  • Streptococcus pneumoniae / growth & development
  • Streptococcus pneumoniae / physiology
  • beta-Lactam Resistance* / drug effects


  • Bacterial Proteins
  • Cytoskeletal Proteins
  • FtsZ protein, Bacteria
  • Penicillin-Binding Proteins
  • PBP 2x protein, Streptococcus
  • Aminoacyltransferases
  • penicillin-binding protein 2b, Streptococcus
  • Piperacillin