Principal Investigator (PI)
The Foundation is providing £180,326 in support.
Deborah Kajewole
Laura Dingle
GSK provides scientific and technical expertise required to:
1) Miniaturize the luciferase-based assay for use in HTS applications.
2) Perform target-based and on-target phenotypic HTS using appropriate/relevant GSK chemical libraries and assays developed at Rhodes University.
3) Provide access to mouse models of TB infection for validation of in vivo efficacy.
4) Provide support and training to researchers to increase drug discovery capacity at Rhodes University.
Rationale:
Protein homeostasis requires molecular chaperones to catalyse protein folding to counteract stress-related denaturation. Mycobacterium tuberculosis (Mtb) experiences numerous stresses in host cells that challenge protein homeostasis and lead to a heightened requirement for chaperones1. The Mtb DnaK chaperone complex, comprised of DnaK (MtbDnaK), GrpE (MtbGrpE) and the co-chaperone proteins DnaJ1 (MtbDnaJ1) or DnaJ2 (MtbDnaJ2) contributes to native protein folding, refolding and prevention of protein aggregation in both healthy and stressed mycobacterial cells2-4.
Research Hypothesis:
Genetic studies have shown that the DnaK chaperone complex is essential for mycobacterial growth. This suggests that small molecule inhibition of the chaperone complex would be lethal for Mtb, making this system an attractive target for the development of new drugs to combat tuberculosis.
Research Objectives/Goal:
The project aims to identify new scaffolds that target the Mtb DnaK chaperone complex, which can subsequently serve as a starting point for the development of potent and selective compounds for the treatment of mycobacterial infections.
Problem statement and research question(s):
The MtbDnaK enzyme has been biochemically characterised3 and shown by genetic studies to be essential for the growth and survival of Mtb in vitro and in vivo,5,6. The latter observation suggest that small molecule inhibition of the DnaJ-DnaK-GrpE chaperone complex would be lethal for Mtb, making this system an attractive target for the development of new and selective drugs to combat mycobacterial infections.
Project vision/goal:
The primary aim of this project is to identify new inhibitor scaffolds that target the Mtb DnaK-DnaJ-GrpE complex. Scaffolds that are identified as selective inhibitors of the Mtb chaperone complex will be prioritised for rational modification to identify structure-activity relationships (SAR) designed to improve the potency, selectivity and anti-tubercular activity of inhibitors. These studies, together with additional biochemical and cellular studies designed to determine the mechanism of target engagement, enzyme inhibition, cellular accumulation, and anti-tubercular activity, will potentially result in the identification of inhibitors that can be developed into lead compounds.
Overall, the research project aims to identify a new class of anti-tubercular drugs that operates via inhibition of a novel target and could therefore be useful in combating both drug-sensitive and/or drug-resistant forms of Mtb infections.
[1] Lupoli, T. J. et al. (2018):10.1021/acsinfecdis.7b00231
[2] Fay, A. et al. (2014):10.1371/journal.pgen.1004516
[3] Lupoli, T. J. et al. (2016):10.1073/pnas.1617644113
[4] Stewart, G. R. et al. (2002):10.1099/00221287-148-10-3129
[5] Sassetti, C. M. et al. (2003):10.1046/j.1365-2958.2003.03425
[6] Sassetti, C. M. et al. (2003):10.1073/pnas.2134250100