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Molecular Mechanisms for Host-Mediated Metal Poisoning Detoxification in Mycobacterium tuberculosis

Project description

Novel targets for tuberculosis drug development

Tuberculosis is a bacterial infection caused by Mycobacterium tuberculosis and usually affects the lungs. Although it can be prevented, more than 1 million individuals die each year of tuberculosis. This is due to the lack of effective therapies and the emergence of drug resistance. Funded by the Marie Skłodowska-Curie Actions (MSCA) programme, the MTB-DETOX project proposes to identify novel treatment targets against tuberculosis. The work focuses on the zinc detoxification pathways that are important for M. tuberculosis survival in macrophages. Researchers will characterise proteins implicated in this pathway using a multidisciplinary approach, unveiling new opportunities for tuberculosis drug development.


Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) kills 1.5 million people every year. Major challenges facing TB eradication are the lack of effective and affordable treatments, the slow pace of innovation in TB drug discovery and the emergence of antibiotics resistance. Therefore, new approaches for addressing these challenges are urgently needed. Mtb is highly adapted to survive into human macrophages which expose the bacterium to many stresses including metal ion in-toxification, whereby the host cell increases its metal ion levels resulting in inflow of metal ions into Mtb. The host laboratory has previously demonstrated that the P-ATPase transporter CtpC is part of the metal efflux system involved in zinc detoxification, which is important for Mtb survival in macrophages. Intriguingly, CtpC and two other P-ATPases are encoded together with small proteins containing a domain of unknown function named DUF1490. Unpublished data show that the DUF1490 protein encoded with CtpC binds zinc and confers zinc in-toxification tolerance to Mtb. Additionally, DUF1490 proteins co-localize with CtpC to the plasma membrane into dynamic microdomains, named “metal efflux platforms”. I propose to uncover the function of DUF1490 proteins by testing two hypotheses: 1) DUF1490 proteins are metallochaperones that facilitate the intracellular transport of metal ions to membrane transporters, and 2) DUF1490 proteins are scaffold proteins involved in P-ATPase stabilization and metal efflux platforms assembly. To explore these hypotheses, I will combine genetic, microbiology and molecular biology strategies with high-resolution optical imaging, lipidomics and proteomics. Rigorous execution of the proposed research will generate insights into the role of DUF1490 proteins in Mtb metal detoxification and pathogenicity, as well as into the novel concept of metal efflux platforms, thus yielding opportunities for TB drug development that go beyond traditional targets.


Net EU contribution
€ 195 914,88
75794 Paris

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Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
Total cost
No data

Partners (2)