Molecular Mechanisms of Sulbactam Antibacterial Activity and Resistance Determinants in Acinetobacter baumannii

Abstract

ABSTRACTSulbactam is a class A β-lactamase inhibitor with intrinsic whole-cell activity against certain bacterial species, includingAcinetobacter baumannii. The clinical use of sulbactam forA. baumanniiinfections is of interest due to increasing multidrug resistance in this pathogen. However, the molecular drivers of its antibacterial activity and resistance determinants have yet to be precisely defined. Here we show that the antibacterial activities of sulbactam vary widely across contemporaryA. baumanniiclinical isolates and are mediated through inhibition of the penicillin-binding proteins (PBPs) PBP1 and PBP3, with very low frequency of resistance; the rarepbp3mutants with high levels of resistance to sulbactam are attenuated in fitness. These results support further investigation of the potential clinical utility of sulbactam.