Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is now the leading cause of death from infectious disease worldwide. The pathogen’s life cycle is defined by the transition to a persistent state that eludes host defences and drug treatment. The organism can only maintain such states by balancing redox and energy metabolism within host tissues, and disruption of these processes by clinical agents proves bactericidal. A unique aspect of the redox metabolism in M. tuberculosis is the use of a special electron carrier, F420; this cofactor has been shown to mediate at least three processes critical for persistence: redox homeostasis, energy metabolism, and antimicrobial defences. The conditional essentiality of F420 in mycobacteria, combined with its absence from human cells and gut microbiota, suggests the F420 biosynthesis pathway is an excellent next-generation drug target. In this NHMRC New Investigator project, we will develop F420 biosynthesis enzymes as drug targets for tuberculosis treatment. This will be achieved through three interrelated aims that will confirm the biochemistry, essentiality, and druggability of this pathway in M. tuberculosis. These results will provide important insights into the molecular basis of mycobacterial persistence and may justify larger-scale targeted drug development.
|Effective start/end date||1/01/18 → 30/06/21|
- National Health & Medical Research Council (NHMRC): AUD396,024.00