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Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection
11:56

Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection

Published on: October 25, 2013

Replacement of the essential penicillin-binding protein 5 by high-molecular mass PBPs may explain

S al-Obeid1, D Billot-Klein, J van Heijenoort

  • 1Laboratoire de Microbiologie Médicale, Université Paris VI, France.

FEMS Microbiology Letters
|February 1, 1992
PubMed

Insights

Penicillin and vancomycin synergy in resistant E. faecium occurs because high-affinity penicillin-binding proteins (PBPs) compensate for reduced PBP5 function after vancomycin resistance is induced.

Area of Science:

  • Microbiology
  • Antibiotic Resistance
  • Biochemistry

Background:

  • Penicillin-resistant Enterococcus faecium (E. faecium) poses a significant clinical challenge.
  • Vancomycin resistance in E. faecium is often mediated by inducible resistance mechanisms.
  • Understanding antibiotic synergy is crucial for developing effective treatment strategies.

Purpose of the Study:

  • To elucidate the mechanism of synergy between vancomycin and penicillin in a vancomycin-resistant E. faecium strain.
  • To investigate the role of penicillin-binding proteins (PBPs) in this synergistic interaction.

Main Methods:

  • Utilized a penicillin-resistant E. faecium strain (D366) with inducible vancomycin resistance.
  • Assessed the effect of penicillin on the expression of vancomycin resistance determinants (VANB protein and carboxypeptidase activity).
  • Performed competition assays with radiolabeled penicillin and various beta-lactam antibiotics to study PBP binding affinities.

Main Results:

  • Penicillin alone did not reduce the inducible expression of the VANB protein or associated carboxypeptidase activity.
  • Synergy is explained by the shift in function to high-molecular mass PBPs (potentially PBP1) with high beta-lactam affinity.
  • These high-affinity PBPs assume the role of the low-affinity PBP5, which confers resistance in the non-induced state.

Conclusions:

  • The synergy between vancomycin and penicillin in this E. faecium strain is not due to reduced vancomycin resistance gene expression.
  • The mechanism involves a functional compensation by high-affinity PBPs once vancomycin resistance is induced.
  • This highlights the complex interplay of PBPs in antibiotic resistance and synergy.

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