Cryo-EM structure and complementary drug efflux activity of the Acinetobacter baumannii multidrug efflux pump AdeG

Zhenlin Ouyang; Wenbo He; Di Wu; Hao An; Lei Duan; Min Jiao; Xiaoyu He; Qinyue Yu; Jiaxin Zhang; Qian Qin; Ruochen Wang; Fang Zheng; Peter M Hwang; Xiaoting Hua; Li Zhu; Yurong Wen

doi:10.1016/j.str.2024.12.009

Cryo-EM structure and complementary drug efflux activity of the Acinetobacter baumannii multidrug efflux pump AdeG

Structure. 2024 Dec 31:S0969-2126(24)00544-6. doi: 10.1016/j.str.2024.12.009. Online ahead of print.

Authors

Zhenlin Ouyang¹, Wenbo He¹, Di Wu², Hao An², Lei Duan², Min Jiao¹, Xiaoyu He³, Qinyue Yu¹, Jiaxin Zhang³, Qian Qin¹, Ruochen Wang¹, Fang Zheng³, Peter M Hwang⁴, Xiaoting Hua⁵, Li Zhu⁶, Yurong Wen⁷

Affiliations

¹ Center for Microbiome Research of Med-X Institute, Department of Critical Care Medicine, Shaanxi Provincial Key Laboratory of Sepsis in Critical Care Medicine, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
² Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
³ The Key Laboratory of Environment and Genes Related to Disease of Ministry of Education Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China.
⁴ Departments of Medicine and Biochemistry, Faculty of Medicine & Dentistry, Edmonton, AB T6G 2R3, Canada.
⁵ Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁶ Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou 730000, China; Electron Microscopy Centre of Lanzhou University, Lanzhou University, Lanzhou 730000, China. Electronic address: [email protected].
⁷ Center for Microbiome Research of Med-X Institute, Department of Critical Care Medicine, Shaanxi Provincial Key Laboratory of Sepsis in Critical Care Medicine, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China; The Key Laboratory of Environment and Genes Related to Disease of Ministry of Education Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China. Electronic address: [email protected].

PMID: 39798571
DOI: 10.1016/j.str.2024.12.009

Abstract

Multidrug-resistant Acinetobacter baumannii has emerged as one of the most antibiotic-resistant bacterial pathogens associated with nosocomial infection, with its resistance highly depending on multiple multidrug efflux pumps. Here, we report the cryoelectron microscopy (cryo-EM) structure of Acinetobacter drug efflux G (AdeG), the inner membrane component of one of three important resistance-nodulation-cell division (RND) pump family members in A. baumannii, which is involved in drug resistance to chloramphenicol, trimethoprim, ciprofloxacin, and clindamycin. We systematically compare the structures and substrate binding specificities of AdeG, AdeB, and AdeJ multidrug efflux pumps via molecular docking, revealing potential determinants for drug binding. Knockout experiments demonstrate a functional complementarity between AdeABC, AdeFGH, and AdeIJK. Our study provides a structural understanding of A. baumannii multidrug efflux pump AdeG and reveals complementary drug efflux activity between AdeG and other RND efflux pumps, which may promote further rational drug discovery efforts targeting multidrug efflux pumps.

Keywords: Acinetobacter baumannii; AdeG; cryoelectron microscopy; efflux pump; multidrug resistance.