Molecular investigation of siderophore secretion and drug efflux by Mycobacterium tuberculosis

Project Summary - Molecular investigation of siderophore secretion and drug efflux by Mycobacterium tuberculosis Iron is essential for growth of Mycobacterium tuberculosis, but most iron in the human body is tightly bound to proteins. The presence of many iron-sequestering proteins and other iron-restricting factors in the lung granulomas of tuberculosis patients establishes an iron-deprived environment for M. tuberculosis in the human host. To prevent iron starvation, M. tuberculosis secretes siderophores, small molecules with high iron-binding affinities called mycobactins and carboxy-mycobactins. Our extensive preliminary data revealed that siderophore secretion is mediated in M. tuberculosis by a multiprotein complex composed of the inner membrane proteins MmpL4 or MmpL5 and other proteins, whose molecular organization is strikingly different from analogous systems in other bacteria. Overproduction of this secretion system during tuberculosis chemotherapy is also the main resistance mechanism against bedaquiline, a key drug for treatment of infections with multi-drug resistant M. tuberculosis. Intriguingly, mutational analysis revealed that the mycobactin binding pocket of MmpL4 and MmpL5 is also essential for bedaquiline efflux. The proposed research will shed light on this unique secretion system and reveal the molecular mechanisms of siderophore secretion and drug efflux in M. tuberculosis.