Introducing tetracycline as a potential OXA-48 carbapenemase inhibitor: an in silico and in vitro approach.

The emergence of OXA-48 carbapenemase has significantly compromised the effectiveness of carbapenems in treating drug-resistant Gram-negative infections, highlighting an urgent need for novel therapeutic strategies due to the limitations of currently available β-lactam inhibitors against this enzyme. To address this issue, the present study aimed to identify new inhibitors of OXA-48 carbapenemase. Structure-based virtual screening of a library of bacterial secondary metabolites, using molecular docking, was performed to evaluate the ability of these metabolites to inhibit OXA-48 carbapenemase. The screening discovered several promising lead compounds with favorable docking scores of - 9.8 kcal/mol or lower, which were further evaluated through molecular dynamics simulations. Structural analysis of the top lead compound, Tetracenoquinocin, revealed notable structural similarity between this compound and the Tetracycline class of antibiotics, leading to the investigation of Tetracycline as a repurposing candidate. Comparative docking scores and molecular dynamics simulations demonstrated that the OXA-48/Tetracycline complex exhibited superior binding stability, with a more consistent RMSD profile and stronger hydrogen-bonding interaction (4-6 H-bonds) compared to the Tetracenoquinocin complex. These computational findings were validated by in vitro analyses, where a combination of Tetracycline and Meropenem successfully reduced the minimum inhibitory concentration of Meropenem for clinical Klebsiella pneumoniae isolates harboring the bla