Active site electrostatic effects modulate DBO inhibitor potency against OXA-48 variants

Nacubactam shows a higher covalent inhibition energy barrier than avibactam against OXA-48-like class D beta-lactamases, linked to DBO-specific active-site electric field effects.

• Why it matters: Mutations in OXA-48 and its variants alter how class D beta-lactamases process antibiotics, yet DBO inhibitor potency differs, with nacubactam consistently less potent than avibactam.
• What they did: The authors used multiscale simulations, including QM/MM MD, after identifying the second step of DBO acylation as rate-limiting, and combined covalent reaction-rate and non-covalent binding predictions.
• The result: Electrostatic repulsion between the positively charged nacubactam tail and Arg214 in the beta5-beta6 loop weakens binding, reproduces the experimental IC50 order across OXA-48 variants, and predicts potency against OXA-517.

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