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

Jules Philippe1, Benoit Gallet1, Cécile Morlot1

  • 1Université Grenoble Alpes, IBS, Grenoble, France CNRS, IBS, Grenoble, France CEA, IBS, Grenoble, France.

Antimicrobial Agents and Chemotherapy
|November 12, 2014
PubMed

Insights

Piperacillin, a β-lactam antibiotic, paradoxically targets Streptococcus pneumoniae's PBP2x but selects for PBP2b variants. This study models how this affects peptidoglycan assembly and cell shape.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Biochemistry

Background:

  • Streptococcus pneumoniae resistance to β-lactam antibiotics is widespread.
  • This resistance is mediated by mosaic variants of penicillin-binding proteins (PBPs).
  • Understanding β-lactam action is crucial for developing new drugs and counter-resistance strategies.

Purpose of the Study:

  • Investigate the piperacillin paradox in Streptococcus pneumoniae.
  • Explain why piperacillin selects for PBP2b variants despite PBP2x being its primary target.
  • Propose a model for peptidoglycan assembly accounting for piperacillin's effects.

Main Methods:

  • Electron microscopy of treated and untreated Streptococcus pneumoniae cells.
  • Epifluorescence microscopy to determine PBP localization.
  • Time-course determination of PBP inhibition by piperacillin.

Main Results:

  • Piperacillin treatment induces "lemon"-shaped cells, consistent with PBP2x inhibition.
  • Piperacillin primarily selects for PBP2b variants.
  • PBP2x and PBP2b are essential monofunctional transpeptidases in peptidoglycan assembly.

Conclusions:

  • A model of peptidoglycan assembly is proposed to explain the piperacillin paradox.
  • The model reconciles the differential selection and targeting of PBP2b and PBP2x.
  • This research provides insights into antibiotic resistance mechanisms and drug development.

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