Assembly and inhibition of transferable TMexCD1-TOprJ1 efflux pump

Yu Shi, Mengyuan Li, Tao Cui, Jianhua Gan (), Haomin Huang, Zhi Su, Runshi Yang, Xing Zhang, Huimin Zhang, Yu Feng () and Youjun Feng ()
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Yu Shi: Zhejiang University School of Medicine
Mengyuan Li: Zhejiang University School of Medicine
Tao Cui: Northwestern Polytechnical University
Jianhua Gan: Fudan University
Haomin Huang: Zhejiang University School of Medicine
Zhi Su: Zhejiang University School of Medicine
Runshi Yang: Zhejiang University School of Medicine
Xing Zhang: Zhejiang University
Huimin Zhang: University of Illinois at Urbana-Champaign
Yu Feng: Zhejiang University School of Medicine
Youjun Feng: Zhejiang University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract Recent emergence and dissemination of plasmid-borne tmexCD1-toprJ1 tigecycline resistance threatens the efficacy of tigecycline as a “last-resort” defense against bacterial infections. Here, we report two cryo-EM structures of TMexCD1-TOprJ1 alone and in complex with its NMP inhibitor, and both are determined at the resolutions of 2.97 Å and 3.0 Å, respectively. The symmetry of overall architecture explains how the tripartite organization adopts a 3:6:3 protomer stoichiometry (TOprJ1: TMexC1: TMexD1) to assemble an elongated, rod-like pump spanning bacterial double membranes. The periplasmic TMexC1 adaptor bind the trimeric TOprJ1 funnel via a universal “tip-to-tip” contact, and bridges the bottom TMexD1 engine by extensive interactions. A unique form of resting (R) states is observed for TMexD1 trimer. Besides two binding-interfaces of TMexC1 with TOprJ1 and TMexD1, we characterize a substrate/inhibitor-loading cavity. Collectively, these findings constitute molecular bases for assembly and inhibition of transferable TMexCD1-TOprJ1 machinery, and benefit developing next-generation of antimicrobials targeting functional efflux pump.

Date: 2025
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DOI: 10.1038/s41467-025-65038-x

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