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

Objective

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 Unpublished data show that the DUF1490 protein encoded with CtpC binds zinc and confers zinc in-toxification tolerance to Mtb.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.

Coordinator

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Net EU contribution
€ 195 914,88
Address
Rue Michel Ange 3
75794 Paris
France

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Region
Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
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Partners (2)

UNIVERSITE PAUL SABATIER TOULOUSE III
France
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Address
Route De Narbonne 118
31062 Toulouse Cedex 9

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Region
Occitanie Midi-Pyrénées Haute-Garonne
Activity type
Higher or Secondary Education Establishments
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UNIVERSITE DE BORDEAUX
France
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No data
Address
Place Pey Berland 35
33000 Bordeaux

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Region
Nouvelle-Aquitaine Aquitaine Gironde
Activity type
Higher or Secondary Education Establishments
Other funding
No data