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Kinetic analysis of Enterococcus faecium L,D-transpeptidase inactivation by carbapenems

Vincent Dubée1, Michel Arthur, Hélène Fief

  • 1Centre de Recherche des Cordeliers, LRMA, Équipe 12, Université Pierre et Marie Curie, Paris, France.

Antimicrobial Agents and Chemotherapy
|March 28, 2012
PubMed

Insights

Enterococcus faecium uses L,D-transpeptidase (Ldt(fm)) to resist ampicillin. Researchers studied how carbapenems interact with Ldt(fm), finding bulky side chains affect drug binding and enzyme hydrolysis.

Area of Science:

  • Microbiology
  • Drug Resistance
  • Biochemistry

Background:

  • Enterococcus faecium exhibits high-level ampicillin resistance due to bypass of penicillin-binding proteins by L,D-transpeptidase (Ldt(fm)).
  • Carbapenems are currently the most effective beta-lactam antibiotics against E. faecium strains with Ldt(fm).

Purpose of the Study:

  • To investigate the kinetic mechanisms of L,D-transpeptidase inactivation by various carbapenems.
  • To elucidate the role of carbapenem structure, specifically side chain modifications, in Ldt(fm) inhibition.

Main Methods:

  • Kinetic analysis of Ldt(fm) inactivation.
  • Comparison of four commercial carbapenems and a modified derivative.
  • Evaluation of acyl-enzyme hydrolysis and drug-binding interactions.

Main Results:

  • Carbapenem structure significantly influences the rate and mechanism of Ldt(fm) inactivation.
  • Bulky side chains on carbapenems present a dual effect: hindering hydrolysis but potentially impairing drug binding.
  • A carbapenem derivative with a minimal ethyl group at position 2 showed altered interaction kinetics.

Conclusions:

  • Understanding carbapenem-Ldt(fm) interactions is crucial for developing new antibiotics against resistant E. faecium.
  • Structural modifications of carbapenems can modulate their efficacy against Ldt(fm).
  • Further research into optimizing carbapenem structure is warranted to overcome resistance mechanisms.

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