The scientists: Dr. Avishek Mitra, Bjorn Sunde and Prof. Michael Niederweis will focus their research on the identification of small molecules that kill Mycobacterium tuberculosis by inhibiting siderophore efflux. Dr. Mitra is a postdoctoral researcher working on iron acquisition by M. tuberculosis in the laboratory of Prof. Niederweis in the Department of Microbiology at the University of Alabama at Birmingham. Bjorn Sunde is a research assistant with experience in performing high-throughput screening assays in Biosafety Level 3 laboratories.
The sponsors: University of Alabama at Birmingham, Department of Microbiology.
Foundation funding: The Foundation is providing £213,119 in support.
GSK’s contribution: GSK will provide access to biosafety level 3 and high-throughput screening facilities, microbiology and drug discovery expertise as well as full access to antimycobacterial compound sets.
Project Description: 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.