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Bio-layer Interferometry for Measuring Kinetics of Protein-protein Interactions and Allosteric Ligand Effects
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Electrostatic interactions influence diazabicyclooctane inhibitor potency against OXA-48-like β-lactamases

Joseph F Hoff1, Kirsty E Goudar1, Karina Calvopiña2

  • 1School of Cellular and Molecular Medicine, University of Bristol Bristol BS8 1TD UK Jim.Spencer@bristol.ac.uk.

RSC Medicinal Chemistry
|September 10, 2025
PubMed

Insights

New diazabicyclooctane (DBO) inhibitors, avibactam and nacubactam, show varying potency against OXA-48-like carbapenemases. Arg214 in OXA-48 influences nacubactam binding, impacting treatment strategies for resistant bacterial infections.

Area of Science:

  • Biochemistry and Molecular Biology
  • Antimicrobial Resistance
  • Structural Biology

Background:

  • Carbapenemase-producing Enterobacterales are a significant threat to public health, complicating treatment of multi-drug resistant bacterial infections.
  • OXA-48 carbapenemase is a prevalent enzyme conferring resistance to carbapenem antibiotics.
  • Diazabicyclooctane (DBO) inhibitors like avibactam and nacubactam are crucial for overcoming β-lactamase-mediated resistance.

Purpose of the Study:

  • To investigate the inhibitory mechanisms of avibactam and nacubactam against OXA-48 and its variants (OXA-163, OXA-405).
  • To elucidate the structural basis for differential inhibition, particularly the role of the β5-β6 loop.
  • To understand how sequence variations in OXA-48-like enzymes affect inhibitor reactivity.

Main Methods:

  • Enzyme inhibition assays to determine the potency of avibactam and nacubactam against OXA-48, OXA-163, and OXA-405.
  • X-ray crystallography and molecular dynamics simulations to visualize and analyze enzyme-inhibitor interactions.
  • Mass spectrometry to investigate the desulfation of bound DBOs by the enzymes.

Main Results:

  • Nacubactam showed significantly lower potency against OXA-48 compared to avibactam, a difference that diminished with OXA-163 and OXA-405.
  • Structural analysis revealed electrostatic repulsion between Arg214 in OXA-48 and nacubactam, which was absent in OXA-163 and OXA-405 due to the lack of Arg214.
  • All tested enzymes were found to desulfate bound DBOs, indicating a common inactivation pathway.

Conclusions:

  • The presence of Arg214 in the OXA-48 β5-β6 loop is a key determinant of differential DBO inhibitor potency.
  • Sequence variations in OXA-48-like β-lactamases can alter their interaction with inhibitors, influencing therapeutic efficacy.
  • Understanding these structure-activity relationships is vital for developing next-generation carbapenemase inhibitors.

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