Repurposing a drug to punish carbapenem-resistant Acinetobacter baumannii
- Jennifer M. Colquhoun
- Carter U. Brzezinski
- Andrew Ji
- Julianna Marotta
- Franziska A. V. Elsen
- Robert A. Bonomo
- Kerrie L. May
- Stephan A. Sieber
- Marcin Grabowicz
- William M. Wuest
- Philip N. Rather
2025-06-10
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.