Biological Sciences Division
Published April 29, 2024 | Version v1
Journal article Open

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

Creators

  • 1. Université Paris Cité
  • 2. Sapienza University of Rome
  • 3. University of Chicago
  • 4. Université de Toulouse
  • 5. Université de Lille

Description

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.

Data availability

All relevant data are within the paper and its Supporting information files. The RNA-Seq fastq files have been deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO Series accession number GSE222412.

Files

journal.pbio.3002259.pdf

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Additional details

Identifiers

DOI
10.1371/journal.pbio.3002259
Other
oai:uchicago.tind.io:11819

Funding

Institut Pasteur
Unknown funder
Georges, Jacques and Elias Canetti Award
French National Research Agency
20-PAMR-0005
Fondation pour la Recherche Médicale
FRM FDM201806006250
Sapienza Ateneo Project 2021
RM12117A61C811CE
Regione Lazio PROGETTI DI GRUPPI DI RICERCA 2020
A0375-2020-36597
Unknown funder
FISR2019_00374 MeDyCa

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Genetics, Genomics, and Systems Biology, Immunology, Medicine