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.

Colquhoun, Jennifer M., Carter U. Brzezinski, Andrew Ji, Julianna Marotta, Franziska AV Elsen, Robert A. Bonomo, Kerrie L. May et al. "Repurposing a drug to punish carbapenem-resistant Acinetobacter baumannii." Proceedings of the National Academy of Sciences, 122(24), e2423650122 (2025).

Link: https://doi.org/10.1073/pnas.2423650122

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