Determination of potential combination of non‐β‐lactam, β‐lactam, and β‐lactamase inhibitors/β‐lactam enhancer against class D oxacillinases producing Acinetobacter baumannii: Evidence from in‐vitro, molecular docking and dynamics simulation

Abstract Carbapenem‐resistant Acinetobacter baumannii , a predominant nosocomial pathogen in hospitals of intensive care units, is associated with bacteremia and ventilator‐associated pneumonia with a high‐risk mortality rate. To increase the effectiveness of the β‐lactam (BL) antibiotics, the use of β‐lactamase inhibitors (BLI) acts as a booster when given in combination with BL antibiotics. To this aspect, we selected BL antibiotics of cefiderocol, cefepime, non‐BL antibiotic eravacycline, BLI of durlobactam, avibactam, and a β‐lactam enhancer (BLE) of zidebactam. To prove our hypothesis, we determined the minimum inhibitory concentration (MIC) of various BL or non‐BL/BLI or BLE combinations using broth microdilution method followed by in silico analysis of molecular docking, molecular dynamics (MD) simulation, and molecular mechanics Poisson–Boltzmann surface area (MM‐PBSA) identifies the potential combination. In MIC testing, eravacycline, cefepime/zidebactam, cefiderocol/zidebactam, and eravacycline in combination with zidebactam or durlobactam were found to be effective against oxacillinases (OXAs) (OXA‐23/24/58 like) expressing A. baumannii isolates. The docking results of the selected ligands toward OXA‐23, OXA‐24, and OXA‐58 had an excellent binding score ranging from −5.8 to −9.3 kcal/mol. Further, the docked complexes were subjected and evaluated using gromacs for molecular dynamics simulation of 50 ns toward selected class D OXAs. The binding energies obtained from MM‐PBSA shed light on the binding efficiencies of each non‐BL, BL, and BLI/BLE, thereby helping us to propose the drug combinations. Based on the MD trajectories scoring acquired, we propose using eravacycline, cefepime/zidebactam, cefiderocol/zidebactam, and eravacycline in combination with durlobactam or zidebactam would be promising for treating OXA‐23, OXA‐24, and OXA‐58 like expressing A. baumannii infections.