Discovery of dual-active ethionamide boosters inhibiting the Mycobacterium tuberculosis ESX-1 secretion system.

Autor:	Gries R; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, 50931 Cologne, Germany., Chhen J; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany., van Gumpel E; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany., Theobald SJ; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany., Sonnenkalb L; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, 23845 Borstel, Germany; Molecular and Experimental Mycobacteriology, Research Center Borstel, Leibniz Lung Center, 23845 Borstel, Germany., Utpatel C; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, 23845 Borstel, Germany; Molecular and Experimental Mycobacteriology, Research Center Borstel, Leibniz Lung Center, 23845 Borstel, Germany., Metzen F; Institute for Dental Research and Oral Musculoskeletal Biology, Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany., Koch M; Institute for Dental Research and Oral Musculoskeletal Biology, Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany., Dallenga T; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, 23845 Borstel, Germany; Cellular Microbiology, Research Center Borstel, Leibniz Lung Center, 23845 Borstel, Germany., Djaout K; University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Center for Infection and Immunity of Lille, 59000 Lille, France., Baulard A; University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Center for Infection and Immunity of Lille, 59000 Lille, France., Dal Molin M; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany., Rybniker J; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, 50931 Cologne, Germany. Electronic address: jan.rybniker@uk-koeln.de.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2024 Apr 18; Vol. 31 (4), pp. 699-711.e6. Date of Electronic Publication: 2024 Jan 04.
DOI:	10.1016/j.chembiol.2023.12.007
Abstrakt:	Drug-resistant Mycobacterium tuberculosis (Mtb) remains a major public health concern requiring complementary approaches to standard anti-tuberculous regimens. Anti-virulence molecules or compounds that enhance the activity of antimicrobial prodrugs are promising alternatives to conventional antibiotics. Exploiting host cell-based drug discovery, we identified an oxadiazole compound (S3) that blocks the ESX-1 secretion system, a major virulence factor of Mtb. S3-treated mycobacteria showed impaired intracellular growth and a reduced ability to lyse macrophages. RNA sequencing experiments of drug-exposed bacteria revealed strong upregulation of a distinct set of genes including ethA, encoding a monooxygenase activating the anti-tuberculous prodrug ethionamide. Accordingly, we found a strong ethionamide boosting effect in S3-treated Mtb. Extensive structure-activity relationship experiments revealed that anti-virulence and ethionamide-boosting activity can be uncoupled by chemical modification of the primary hit molecule. To conclude, this series of dual-active oxadiazole compounds targets Mtb via two distinct mechanisms of action. Competing Interests: Declaration of interests R.G., J.C., and J.R. have a patent pending related to this work. (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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