Descripción del proyecto
Nuevos objetivos para el desarrollo de fármacos contra la tuberculosis
La tuberculosis es una infección bacteriana causada por el «Mycobacterium tuberculosis» y suele afectar a los pulmones. Aunque se puede prevenir, más de un millón de personas mueren cada año de tuberculosis. Ello se debe a la falta de tratamientos eficaces y a la aparición de la farmacorresistencia. El equipo del proyecto MTB-DETOX, financiado por las Acciones Marie Skłodowska-Curie, propone identificar nuevas dianas terapéuticas contra la tuberculosis. El trabajo se centra en las vías de desintoxicación del zinc que son importantes para la supervivencia de «M. tuberculosis» en los macrófagos. Los investigadores caracterizarán las proteínas implicadas en esta vía mediante una metodología multidisciplinar, lo que permitirá descubrir nuevas posibilidades para el desarrollo de fármacos contra la tuberculosis.
Objetivo
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 Unpublished data show that the DUF1490 protein encoded with CtpC binds zinc and confers zinc in-toxification tolerance to Mtb.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.
Ámbito científico
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- natural scienceschemical sciencesinorganic chemistrytransition metals
- medical and health sciencesclinical medicinepneumologytuberculosis
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibiotics
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistanceantibiotic resistance
Palabras clave
Programa(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régimen de financiación
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinador
75794 Paris
Francia