Novel Sulbactam Combinations Against Multidrug-Resistant Acinetobacter Baumannii

Multidrug-resistant (MDR) Acinetobacter baumannii poses a critical threat in healthcare settings due to its capacity to evade commonly used antibiotics, particularly through the production of various beta-lactamases. Sulbactam, a beta-lactamase inhibitor with intrinsic bactericidal activity, often requires combination with beta-lactamase inhibitors to restore efficacy. This study investigates the synergistic potential of combining Sulbactam with novel inhibitors—Durlobactam, Avibactam, and ETX۲۵۱۴—against Class A, Class C, and Class D beta-lactamases. Molecular docking, molecular dynamics (MD) simulations, and MM/PBSA binding energy calculations were performed to evaluate the binding affinities of the inhibitors to their respective beta-lactamases. The Chou-Talalay method was applied to assess synergy by calculating Combination Index (CI) values, with CI < ۱ indicating synergy. Durlobactam + Sulbactam demonstrated superior synergy compared to other combinations, with a CI of ۰.۶۲ against Class D, while ETX۲۵۱۴ + Sulbactam exhibited broad-spectrum synergy across all beta-lactamase classes (CI < ۰.۸۰). Avibactam + Sulbactam showed limited synergy against Class D enzymes (CI = ۱.۰۹) but remained effective against Class A and Class C beta-lactamases. The molecular dynamics and MM/PBSA calculations supported these findings, with ETX۲۵۱۴ and Durlobactam showing superior binding stability in the active sites. This study demonstrates the potential of Durlobactam and ETX۲۵۱۴ as highly effective beta-lactamase inhibitors when combined with Sulbactam, particularly against Class D beta-lactamases in MDR Acinetobacter baumannii. These findings highlight the importance of selecting appropriate inhibitors to restore antibiotic efficacy and suggest Sulbactam + ETX۲۵۱۴ as a promising therapeutic option for MDR infections.

کلیدواژه ها:

Acinetobacter baumannii ، Multidrug-resistant infections synergism ، beta-lactamase inhibitors ، Molecular docking ، Molecular Dynamics Simulation ، Combination index analysis