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Author Spotlight: Advancing Antibiotic Resistance Research Using an Efflux-Deficient Bacterial Strain and a Single-Copy Gene Expression System
Published on: January 5, 2024
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Assembly and inhibition of transferable TMexCD1-TOprJ1 efflux pump
Yu Shi1,2, Mengyuan Li1,2,3, Tao Cui4
1Department of General Intensive Care Unit of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Nature Communications
|November 14, 2025
Summary
Tigecycline resistance mediated by the TMexCD1-TOprJ1 efflux pump is a growing threat. Cryo-EM structures reveal the pump
Area of Science:
- Structural Biology
- Microbiology
- Drug Resistance
Background:
- Plasmid-borne tmexCD1-toprJ1 confers tigecycline resistance, compromising last-resort antibiotic efficacy.
- Understanding the molecular mechanisms of this efflux pump is crucial for combating bacterial infections.
Purpose of the Study:
- To determine the cryo-electron microscopy (cryo-EM) structures of the TMexCD1-TOprJ1 efflux pump.
- To elucidate the molecular basis of TMexCD1-TOprJ1 assembly and inhibition by NMP.
Main Methods:
- Two cryo-EM structures of TMexCD1-TOprJ1 were determined at 2.97 Å and 3.0 Å resolution.
- Analysis of the tripartite pump architecture, protomer stoichiometry (3:6:3), and inter-component interactions.
Main Results:
- Revealed a 3:6:3 protomer stoichiometry (TOprJ1:TMexC1:TMexD1) forming an elongated, rod-like pump.
- Identified TMexC1's role as a periplasmic adaptor bridging TOprJ1 and the TMexD1 engine.
- Characterized a unique resting state of the TMexD1 trimer and a substrate/inhibitor-loading cavity.
Conclusions:
- Provided molecular insights into the assembly and inhibition of the transferable TMexCD1-TOprJ1 efflux pump.
- Findings support the development of novel antimicrobials targeting this essential drug resistance mechanism.
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