ArticleThe EMBO journal2023
Mechanism of mycobacterial ATP synthase inhibition by squaramides and second generation diarylquinolines.
Article in The EMBO journal, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 36 citations in OpenAlex.
- A Multi-Scale Computational Framework for Anti-Persister Tuberculosis Drug Discovery.Chemical biology & drug design · 2026Review
- Second-Generation Anti-Tubercular Squaramides Targeting Complex V of the Respiratory Chain ofJournal of medicinal chemistry · 2026Article
- Review
- Secondary metabolites fromRSC advances · 2026Article
- Drug Exposure Dictates Evolutionary Dynamics of Drug-Resistant Tuberculosis: A Longitudinal Cohort Study in Beijing, China.Infection and drug resistance · 2026Article
- Bedaquiline resistance-associated genetic mutations and minimum inhibitory concentrations in drug-resistant tuberculosis clinical isolates from Limpopo province, South Africa.Frontiers in microbiology · 2026Article
- Combating Drug Resistance inBioinformatics and biology insights · 2026Article
- Design, Synthesis, and Biological Evaluation of Mono- and Diamino-Substituted Squaramide Derivatives as Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthase.Journal of medicinal chemistry · 2025Article
- Article
- Structure of ATP synthase from an early photosynthetic bacteriumProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Investigation of bedaquiline heteroresistance amongMicrobiology spectrum · 2025Article
- Cryo-EM of native membranes reveals an intimate connection between the Krebs cycle and aerobic respiration in mycobacteria.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- TBAJ-587, a novel diarylquinoline, is active againstAntimicrobial agents and chemotherapy · 2024Article
- Exploring the Chemical Space of Mycobacterial Oxidative Phosphorylation Inhibitors Using Molecular Modeling.ChemMedChem · 2024Review
- 3-[(Benzo-1,3-dioxol-5-yl)amino]-4-methoxycyclobut-3-ene-1,2-dione: polymorphism and twinning of a precursor to an antimycobacterial squaramide.Acta crystallographica. Section C, Structural chemistry · 2024Article
- Article
- Article
- The importance of heteroresistance and efflux pumps in bedaquiline-resistant Mycobacterium tuberculosis isolates from Iran.Annals of clinical microbiology and antimicrobials · 2024Article
- Molecular Modeling and Simulation of the Mycobacterial Cell Envelope: From Individual Components to Cell Envelope Assemblies.The journal of physical chemistry. B · 2023Review
- A tale of two inhibitors: diarylquinolines and squaramides.The EMBO journal · 2023Article
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Mycobacteria, such as Mycobacterium tuberculosis, depend on the activity of adenosine triphosphate (ATP) synthase for growth. The diarylquinoline bedaquiline (BDQ), a mycobacterial ATP synthase inhibitor, is an important medication for treatment of drug-resistant tuberculosis but suffers from off-target effects and is susceptible to resistance mutations. Consequently, both new and improved mycobacterial ATP synthase inhibitors are needed. We used electron cryomicroscopy and biochemical assays to study the interaction of Mycobacterium smegmatis ATP synthase with the second generation diarylquinoline TBAJ-876 and the squaramide inhibitor SQ31f. The aryl groups of TBAJ-876 improve binding compared with BDQ, while SQ31f, which blocks ATP synthesis ~10 times more potently than ATP hydrolysis, binds a previously unknown site in the enzyme's proton-conducting channel. Remarkably, BDQ, TBAJ-876, and SQ31f all induce similar conformational changes in ATP synthase, suggesting that the resulting conformation is particularly suited for drug binding. Further, high concentrations of the diarylquinolines uncouple the transmembrane proton motive force while for SQ31f they do not, which may explain why high concentrations of diarylquinolines, but not SQ31f, have been reported to kill mycobacteria.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.