Principal Investigator (PI)
University of Alabama
The Foundation is providing £257.209 in support.
Mycobacterium tuberculosis (Mtb) acquires iron by secreting siderophores and their subsequent uptake after capturing iron. Two closely related transporters, MmpL4 and MmpL5, are part of a multi-protein complex required for secretion of these mycobactins and for drug efflux. Genetic inactivation of this secretion systems leads to intracellular accumulation of siderophores and self-poisoning of Mtb reducing its virulence in mice by 20,000-fold. Two whole-cell screening assays of a total of ~300,000 compounds identified siderophore-dependent inhibitors and resulted in lead compounds with bactericidal activity against Mtb with MIC90 values ranging from 2 nM to 1 ?M in vitro. These lead compounds inhibit siderophore secretion by Mtb and synergize with tuberculosis drugs such as bedaquiline and rifampicin. This synergy is due to the fact that overproduction of the MmpL5 secretion machinery is the main resistance mechanism of Mtb against bedaquiline. The goal of this project is to comprehensively characterize our siderophore-secretion inhibitors to provide a solid foundation for mouse infection experiments and to develop a drug, which not only kills Mtb by itself but also rescues bedaquiline as a key drug for treating drug-resistant tuberculosis.