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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.

Authors :
Alexandra Maure
Emeline Lawarée
Francesco Fiorentino
Alexandre Pawlik
Saideep Gona
Alexandre Giraud-Gatineau
Matthew J G Eldridge
Anne Danckaert
David Hardy
Wafa Frigui
Camille Keck
Claude Gutierrez
Olivier Neyrolles
Nathalie Aulner
Antonello Mai
Mélanie Hamon
Luis B Barreiro
Priscille Brodin
Roland Brosch
Dante Rotili
Ludovic Tailleux
Source :
PLoS Biology, Vol 22, Iss 4, p e3002259 (2024)
Publication Year :
2024
Publisher :
Public Library of Science (PLoS), 2024.

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.

Subjects

Subjects :
Biology (General)
QH301-705.5

Details

Language :
English
ISSN :
15449173 and 15457885
Volume :
22
Issue :
4
Database :
Directory of Open Access Journals
Journal :
PLoS Biology
Publication Type :
Academic Journal
Accession number :
edsdoj.2eedf80218b48f79d34efc207ddd2fb
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pbio.3002259