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

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Structure Pub Date : 2025-01-10 DOI:10.1016/j.str.2024.12.009

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

{"title":"Cryo-EM structure and complementary drug efflux activity of the Acinetobacter baumannii multidrug efflux pump AdeG","authors":"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","DOIUrl":null,"url":null,"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.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"31 1","pages":""},"PeriodicalIF":4.4000,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Structure","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.str.2024.12.009","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

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.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

鲍曼不动杆菌多药外排泵AdeG的低温电镜结构和补充药物外排活性

多药耐药鲍曼不动杆菌已成为与医院感染相关的最具抗生素耐药性的细菌病原体之一，其耐药性高度依赖于多个多药外排泵。本文报道了鲍曼不动杆菌药物外排G （AdeG）的低温电镜结构，AdeG是鲍曼不动杆菌三种重要耐药-结节-细胞分裂（RND）泵家族成员之一的内膜成分，参与对氯霉素、甲氧嘧啶、环丙沙星和克林霉素的耐药。我们通过分子对接系统地比较了AdeG、AdeB和AdeJ多药外排泵的结构和底物结合特异性，揭示了药物结合的潜在决定因素。基因敲除实验表明AdeABC、AdeFGH和AdeIJK之间存在功能互补。本研究提供了鲍曼不动鲍曼多药外排泵AdeG的结构认识，揭示了AdeG与其他RND外排泵之间的药物外排活性互补，为进一步合理发现针对多药外排泵的药物提供了依据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.