Authors
Terezia Kovalova, Sylwia Król, Ana P Gamiz-Hernandez, Dan Sjöstrand, Ville R I Kaila, Peter Brzezinski, Martin Högbom
Published in
Proceedings of the National Academy of Sciences of the United States of America. Volume 121. Issue 47. Pages e2412780121. Nov 19, 2024. Epub Nov 12, 2024.
Abstract
Tuberculosis is one of the most common causes of death worldwide, with a rapid emergence of multi-drug-resistant strains underscoring the need for new antituberculosis drugs. Recent studies indicate that lansoprazole-a known gastric proton pump inhibitor and its intracellular metabolite, lansoprazole sulfide (LPZS)-are potential antituberculosis compounds. Yet, their inhibitory mechanism and site of action still remain unknown. Here, we combine biochemical, computational, and structural approaches to probe the interaction of LPZS with the respiratory chain supercomplex III2IV2 of Mycobacterium smegmatis, a close homolog of Mycobacterium tuberculosis supercomplex. We show that LPZS binds to the Qo cavity of the mycobacterial supercomplex, inhibiting the quinol substrate oxidation process and the activity of the enzyme. We solve high-resolution (2.6 Å) cryo-electron microscopy (cryo-EM) structures of the supercomplex with bound LPZS that together with microsecond molecular dynamics simulations, directed mutagenesis, and functional assays reveal key interactions that stabilize the inhibitor, but also how mutations can lead to the emergence of drug resistance. Our combined findings reveal an inhibitory mechanism of LPZS and provide a structural basis for drug development against tuberculosis.
PMID:
39531492
Bibliographic data and abstract were imported from PubMed on 12 Sep 2026.
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