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A host-directed oxadiazole compound potentiates antituberculosis treatment via zinc poisoning in human macrophages and in a mouse model of infection.
Maure, Alexandra; Lawarée, Emeline; Fiorentino, Francesco; Pawlik, Alexandre; Gona, Saideep; Giraud-Gatineau, Alexandre; Eldridge, Matthew J G; Danckaert, Anne; Hardy, David; Frigui, Wafa; Keck, Camille; Gutierrez, Claude; Neyrolles, Olivier; Aulner, Nathalie; Mai, Antonello; Hamon, Mélanie; Barreiro, Luis B; Brodin, Priscille; Brosch, Roland; Rotili, Dante; Tailleux, Ludovic.
Afiliación
  • Maure A; Institut Pasteur, Université Paris Cité, CNRS UMR 6047, Unit for Integrated Mycobacterial Pathogenomics, Paris, France.
  • Lawarée E; Institut Pasteur, Université Paris Cité, CNRS UMR 6047, Unit for Integrated Mycobacterial Pathogenomics, Paris, France.
  • Fiorentino F; Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy.
  • Pawlik A; Institut Pasteur, Université Paris Cité, CNRS UMR 6047, Unit for Integrated Mycobacterial Pathogenomics, Paris, France.
  • Gona S; Department of Genetic Medicine, University of Chicago, Chicago, Illinois, United States of America.
  • Giraud-Gatineau A; Institut Pasteur, Université Paris Cité, CNRS UMR 6047, Biology of Spirochetes Unit, Paris, France.
  • Eldridge MJG; Institut Pasteur, Université Paris Cité, Chromatine et Infection unit, Paris, France.
  • Danckaert A; Institut Pasteur, Université Paris Cité, UTechS BioImaging-C2RT, Paris, France.
  • Hardy D; Institut Pasteur, Université Paris Cité, Histopathology Platform, Paris, France.
  • Frigui W; Institut Pasteur, Université Paris Cité, CNRS UMR 6047, Unit for Integrated Mycobacterial Pathogenomics, Paris, France.
  • Keck C; Institut Pasteur, Université Paris Cité, CNRS UMR 6047, Unit for Integrated Mycobacterial Pathogenomics, Paris, France.
  • Gutierrez C; Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France.
  • Neyrolles O; Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France.
  • Aulner N; Institut Pasteur, Université Paris Cité, UTechS BioImaging-C2RT, Paris, France.
  • Mai A; Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy.
  • Hamon M; Pasteur Institute, Cenci-bolognetti Foundation, Sapienza University of Rome, Rome, Italy.
  • Barreiro LB; Institut Pasteur, Université Paris Cité, Chromatine et Infection unit, Paris, France.
  • Brodin P; Department of Genetic Medicine, University of Chicago, Chicago, Illinois, United States of America.
  • Brosch R; Université de Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, Lille, France.
  • Rotili D; Institut Pasteur, Université Paris Cité, CNRS UMR 6047, Unit for Integrated Mycobacterial Pathogenomics, Paris, France.
  • Tailleux L; Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy.
PLoS Biol ; 22(4): e3002259, 2024 Apr.
Article en En | MEDLINE | ID: mdl-38683873
ABSTRACT
Antituberculosis drugs, mostly developed over 60 years ago, combined with a poorly effective vaccine, have failed to eradicate tuberculosis. More worryingly, multiresistant strains of Mycobacterium tuberculosis (MTB) are constantly emerging. Innovative strategies are thus urgently needed to improve tuberculosis treatment. Recently, host-directed therapy has emerged as a promising strategy to be used in adjunct with existing or future antibiotics, by improving innate immunity or limiting immunopathology. Here, using high-content imaging, we identified novel 1,2,4-oxadiazole-based compounds, which allow human macrophages to control MTB replication. Genome-wide gene expression analysis revealed that these molecules induced zinc remobilization inside cells, resulting in bacterial zinc intoxication. More importantly, we also demonstrated that, upon treatment with these novel compounds, MTB became even more sensitive to antituberculosis drugs, in vitro and in vivo, in a mouse model of tuberculosis. Manipulation of heavy metal homeostasis holds thus great promise to be exploited to develop host-directed therapeutic interventions.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Oxadiazoles / Tuberculosis / Zinc / Modelos Animales de Enfermedad / Macrófagos / Mycobacterium tuberculosis / Antituberculosos Límite: Animals / Female / Humans Idioma: En Revista: PLoS Biol Asunto de la revista: BIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Francia

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Oxadiazoles / Tuberculosis / Zinc / Modelos Animales de Enfermedad / Macrófagos / Mycobacterium tuberculosis / Antituberculosos Límite: Animals / Female / Humans Idioma: En Revista: PLoS Biol Asunto de la revista: BIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Francia