A 4-methyl-substituted durlobactam analogue as a potential class-D oxacillinase inhibitor in Acinetobacter baumannii—an in silico study

The emergence of extensively drug-resistant Acinetobacter baumannii expressing oxacillinases poses a significant challenge in nosocomial settings. Despite durlobactam being a potent β-lactam inhibitor, its long-term efficacy is limited, particularly against class-D β-lactamase-producing strains. In this study, an integrated computational approach was utilized to characterize a library of durlobactam analogues against two expressed class-D oxacillinases (OXA23 and OXA58) from the whole-genome sequences of pan-Indian clinical isolates. Tanimoto coefficient-based virtual screening identified analogues retaining the key pharmacophoric features of durlobactam. Pharmacokinetics and toxicity profiling indicated favourable drug-like properties with minimal predicted toxicity. Molecular docking and interaction analyses revealed a 4-methyl-substituted durlobactam analogue (CHEMBL3140306) exhibiting strong interactions with active serine residues (S79 for OXA23 and S83 for OXA58) within the conserved S-X-X-K motif that is critical for enzymatic activity of both β-lactamases. Quantum chemical simulations supported the structural stability and favourable reactivity profile of the predicted lead molecule. Molecular dynamics simulation further demonstrated stable and compact binding, characterized by persistent hydrogen bonding and a favourable thermodynamics profile. Binding free calculations and essential dynamics corroborated the affinity and conformational flexibility across both oxacillinases. Overall, in this computational study, we identify a 4-methyl-substituted durlobactam analogue as a promising exploratory inhibitor of oxacillinases, thus offering a basis for further experimental validations.