Repurposing a drug to punish carbapenem-resistant <i>Acinetobacter baumannii</i>.

Abstract

The OXA β-lactamases in <i>Acinetobacter baumannii</i> represent a primary mechanism for resistance to the carbapenems, a class of antibiotics that represent a last line for treatment. In a screen of an U.S. Food and Drug Administration (FDA)-approved drug library, we identified fendiline, a calcium channel blocker, had significantly more antimicrobial activity against OXA-23 expressing cells. Genetic and proteomic studies revealed that fendiline inhibited the essential lipoprotein trafficking pathway (Lol) in both <i>A. baumannii</i> (LolFD) and <i>Escherichia coli</i> (LolCDE). We demonstrate that OXA-23 is an outer membrane lipoprotein and its overexpression resulted in increased lethality in <i>lolFD-</i>depleted <i>A. baumannii</i>. Our results indicate that overexpression of the OXA-23 β-lactamase in <i>A. baumannii</i> stresses normal lipoprotein trafficking, which makes these cells more susceptible to fendiline. Overall, our data reveal a link between carbapenem resistance and the Lol pathway, which can be leveraged for new drug development.