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Common alterations in PBP1a from resistant Streptococcus pneumoniae decrease its reactivity toward beta-lactams:

Viviana Job1, Raphaël Carapito, Thierry Vernet

  • 1Laboratoire des Protéines Membranaires, Institut de Biologie Structurale Jean-Pierre Ebel, Université Joseph Fourier, UMR 5075-CNRS, CEA Grenoble, France.

The Journal of Biological Chemistry
|December 7, 2007
PubMed

Insights

High-level beta-lactam resistance in Streptococcus pneumoniae involves altered PBP1a. Structural analysis reveals a narrower active site cavity and reoriented catalytic residue in resistant strains, impacting drug efficacy.

Area of Science:

  • Microbiology
  • Structural Biology
  • Drug Resistance

Background:

  • Penicillin-binding proteins (PBPs) are crucial targets for beta-lactam antibiotics.
  • High-level beta-lactam resistance in Streptococcus pneumoniae necessitates alterations in multiple PBPs, including PBP1a, PBP2b, and PBP2x.

Purpose of the Study:

  • To elucidate the structural basis of high-level beta-lactam resistance in Streptococcus pneumoniae.
  • To investigate the role of specific mutations in PBP1a on beta-lactam resistance.

Main Methods:

  • Crystal structure determination of soluble PBP1a from a resistant strain (S. pneumoniae 5204).
  • Site-directed mutagenesis to introduce specific PBP1a mutations (T371A and TSQF(574-577)NTGY).
  • In vitro kinetic analysis and in vivo resistance measurements.

Main Results:

  • The crystal structure of PBP1a from resistant S. pneumoniae 5204 revealed a narrower, discontinuous active site cavity compared to susceptible strains.
  • A reorientation of the catalytic residue Ser370 was observed in the resistant PBP1a structure.
  • Investigated mutations (T371A and TSQF(574-577)NTGY) showed altered reaction kinetics and affected resistance levels.

Conclusions:

  • Structural modifications in PBP1a contribute significantly to high-level beta-lactam resistance in Streptococcus pneumoniae.
  • The altered active site cavity and catalytic residue reorientation are key factors in reduced antibiotic susceptibility.

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