OXA-23 β-Lactamase Overexpression in Acinetobacter baumannii Drives Physiological Changes Resulting in New Genetic Vulnerabilities
Jennifer M. Colquhoun, Marjan Farokhyfar, Anna R. Hutcheson, Alexander C. Anderson, Christopher R. Bethel, Robert A. Bonomo, Anthony J. Clarke, Philip N. Rather
Abstract
Acinetobacter baumannii has become a serious pathogen in both hospital and community settings. The β-lactam class of antibiotics is a primary treatment option for A. baumannii infections, and expression of β-lactamases is the most frequent mechanism of resistance in this bacterium. New approaches to treating multidrug-resistant A. baumannii strains are needed. In this study, we demonstrate that overexpressing the OXA-23 β-lactamase leads to significant collateral changes, where peptidoglycan structure is altered. We have identified genes that become selectively essential in OXA-23-expressing strains and confirmed the relationship between altered peptidoglycan and OXA-23 expression by demonstrating that OXA-23 overexpression sensitizes cells to genetic and chemical inhibition of peptidoglycan synthesis. This work paves the way for the identification of new antimicrobial targets, where inhibitors would selectively kill β-lactamase-expressing strains.