Repurposing a drug to punish carbapenem-resistant Acinetobacter baumannii

• 成果类型: Article
• 署名作者: Colquhoun, Jennifer M.; Brzezinski, Carter U.; Ji, Andrew; Marotta, Julianna; Elsen, Franziska A. V.; Bonomo, Robert A.; May, Kerrie L.; Sieber, Stephan A.; Grabowicz, Marcin; Wuest, William M.; Rather, Philip N.
• 署名单位: US Department of Veterans Affairs; Veterans Health Administration (VHA); Atlanta VA Medical Center; Atlanta VA Health Care System; Emory University; Emory University; Emory University; Emory University; Technical University of Munich; University System of Ohio; Case Western Reserve University; US Department of Veterans Affairs; Veterans Health Administration (VHA); Louis Stokes Cleveland Veterans Affairs Medical Center; University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11714
• DOI: 10.1073/pnas.2423650122
• 发表日期: 2025-06-10
• 关键词: outer-membrane lipoprotein; escherichia-coli; pseudomonas-aeruginosa; inhibitors; release; lethal

摘要

The OXA (3-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 (3-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.