A host-directed oxadiazole compound potentiates antituberculosis treatment via zinc poisoning in human macrophages and in a mouse model of infection

by Alexandra Maure, Emeline Lawar ée, 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 Antituberculosis drugs, mostly developed over 60 years ago, combined with a poorly effective vaccine, have failed to eradicate tuberculosis. More worryingly, multiresistant strains ofMycobacterium 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 interv...
Source: PLoS Biology: Archived Table of Contents - Category: Biology Authors: Source Type: research