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 etx2514—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 < 1 indicating synergy. durlobactam + sulbactam demonstrated superior synergy compared to other combinations, with a ci of 0.62 against class d, while etx2514 + sulbactam exhibited broad-spectrum synergy across all beta-lactamase classes (ci < 0.80). avibactam + sulbactam showed limited synergy against class d enzymes (ci = 1.09) but remained effective against class a and class c beta-lactamases. the molecular dynamics and mm/pbsa calculations supported these findings, with etx2514 and durlobactam showing superior binding stability in the active sites. this study demonstrates the potential of durlobactam and etx2514 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 + etx2514 as a promising therapeutic option for mdr infections.