Molecular mechanisms of sulbactam antibacterial activity and resistance determinants in Acinetobacter baumannii

• Published in: Antimicrobial agents and chemotherapy Vol. 59; no. 3; pp. 1680 - 1689
• Main Authors: Penwell, William F, Shapiro, Adam B, Giacobbe, Robert A, Gu, Rong-Fang, Gao, Ning, Thresher, Jason, McLaughlin, Robert E, Huband, Michael D, DeJonge, Boudewijn L M, Ehmann, David E, Miller, Alita A
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01-03-2015
• Subjects: Acinetobacter baumannii; Acinetobacter baumannii - drug effects; Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacology; Drug Resistance, Multiple, Bacterial; Drug Resistance, Multiple, Bacterial - physiology; Mechanisms of Action: Physiological Effects; Penicillin-Binding Proteins - antagonists & inhibitors; Sulbactam; Sulbactam - pharmacology
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/aac.04808-14

Sulbactam is a class A β-lactamase inhibitor with intrinsic whole-cell activity against certain bacterial species, including Acinetobacter baumannii. The clinical use of sulbactam for A. baumannii infections 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 contemporary A. baumannii clinical isolates and are mediated through inhibition of the penicillin-binding proteins (PBPs) PBP1 and PBP3, with very low frequency of resistance; the rare pbp3 mutants with high levels of resistance to sulbactam are attenuated in fitness. These results support further investigation of the potential clinical utility of sulbactam.