title: Molecular mechanisms of sulbactam antibacterial activity and resistance determinants in Acinetobacter baumannii.
abstract: 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.
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Penwell
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Shapiro
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Giacobbe
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: Rong-Fang
authors.initials: RF
authors.lastname: Gu
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Gao
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Thresher
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: McLaughlin
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Huband
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: Boudewijn L M
authors.initials: BL
authors.lastname: DeJonge
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Ehmann
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston, Waltham, Massachusetts, USA alita.miller@astrazeneca.com.
authors.forename: Alita A
authors.initials: AA
authors.lastname: Miller
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial / Q000502:physiology*; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors; D013407:Sulbactam / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D046915:Penicillin-Binding Proteins; D013407:Sulbactam