Repurposing a drug to punish carbapenem-resistant Acinetobacter baumannii Article Swipe
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· 2025
· Open Access
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· DOI: https://doi.org/10.1073/pnas.2423650122
· OA: W4411178061
The OXA β-lactamases in Acinetobacter baumannii 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 A. baumannii (LolFD) and Escherichia coli (LolCDE). We demonstrate that OXA-23 is an outer membrane lipoprotein and its overexpression resulted in increased lethality in lolFD- depleted A. baumannii . Our results indicate that overexpression of the OXA-23 β-lactamase in A. baumannii 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.
