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The OXA-48 beta-lactamase variants show varying carbapenem resistance due to mutations affecting imipenem hydrolysis. Molecular simulations reveal how active site changes influence antibiotic resistance mechanisms.

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Area of Science:

  • Biochemistry and Molecular Biology
  • Computational Chemistry
  • Antimicrobial Resistance

Background:

  • Carbapenem antibiotics are crucial for treating multidrug-resistant infections.
  • OXA-48 beta-lactamase and its variants are significant contributors to carbapenem resistance.
  • Understanding the molecular basis of resistance is vital for developing new therapeutic strategies.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying differential imipenem hydrolysis by OXA-48 variants.
  • To correlate structural mutations in the beta(5)-beta(6) loop with enzymatic activity and carbapenem resistance.
  • To elucidate the role of active site dynamics and hydrogen bonding in imipenem deacylation.

Main Methods:

  • Multiscale simulations combining quantum mechanics/molecular mechanics (QM/MM) for deacylation pathway analysis.
  • Molecular dynamics (MD) simulations to study active site hydrogen bond networks and imipenem binding.
  • Comparison of calculated reaction barriers with experimental kinetic data (K_M and k_cat).

Main Results:

  • OXA-48 variants exhibit distinct imipenem hydrolytic activities, influenced by mutations in the beta(5)-beta(6) loop.
  • Deacylation efficiency is linked to the hydrogen bonding role of deacylating water and hydration of Lys73.
  • Specific mutations in OXA-517, OXA-163, and OXA-405 alter active site interactions, affecting catalytic efficiency and binding affinity.

Conclusions:

  • The study identifies the molecular basis for varying imipenem hydrolysis rates among OXA-48 variants.
  • Active site hydrogen bonding patterns and dynamics are critical determinants of antibiotic resistance.
  • Insights into these interactions can guide the development of novel inhibitors to combat carbapenem resistance.