Principal Investigator (PI)
University of Alabama at Birmingham, Department of Microbiology
The Foundation is providing £313,414 in support.
Dr. Avishek Mitra - Bjorn Sunde
Iron is an essential nutrient for M. tuberculosis which can acquire iron from heme and from its siderophores, mycobactin and carboxymycobactin. This project is based on the surprising finding that blocking siderophore secretion reduces the virulence of Mtb in mice by 10,000-fold. This is one of the strongest virulence defects observed for any Mtb mutant, probably due to the intracellular accumulation of siderophores. Externally added siderophores accumulate in the Mtb secretion mutant and are toxic at submicromolar concentrations. Importantly, this toxicity cannot be overcome by other iron sources such as heme in contrast to Mtb mutants deficient in siderophore biosynthesis. Since siderophore secretion spans both membranes, inhibitors might target this pathway from the outside of the cell and, thereby, might avoid the outer membrane permeability barrier of Mtb.
We have developed a high-throughput screening assay that has identified inhibitors of Mtb whose activity depends on siderophores. These compounds are not detected in whole cell screens under standard conditions. Thus, siderophore secretion appears to be a valuable target for novel TB drugs that will be exploited in this project.