Auckland Cancer Society Research Centre


Medicinal Chemistry - development of novel drugs for the treatment of tuberculosis

Group leader


bacteria

Tuberculosis (TB) is a bacterial infection that is re-emerging as a world health emergency, due in part to its co-occurrence with HIV infection, and the development of treatment-resistant strains of the bacterium. It is estimated that one third of the world’s population is infected with the latent form of TB; of these, each year 9 million people will develop the active, contagious form of the disease, and of these 2-3 million will die from their infection. The current treatment for TB requires that a cocktail of antibiotic drugs be taken continuously for at least six months. There is an urgent need for more active, shorter regimen treatments for TB, particularly against the dormant and drug-resistant forms.

Current research


bedaquiline
  • Bedaquiline is a new clinical agent for the treatment of drug resistant tuberculosis, acting by a novel mechanism by inhibiting ATP synthesis within the bacterium, resulting in depletion of an essential component of the metabolic pathway which the bacterium requires in order to survive. However Bedaquiline has some side effects, including tissue accumulation and cardiotoxicity. Our group was awarded funding from the New York-based Global Alliance for TB Drug Development (GATB) to develop second-generation analogues of Bedaquiline, seeking to identify compounds with more potent activity and an improved safety profile. The Auckland chemistry team, based at the Auckland Cancer Society Research Centre, comprises five medicinal chemists who have to date prepared nearly 1000 compounds for evaluation against cultures of the TB bacterium and in vivo models of the disease. Many highly active compounds with improved physicochemical properties and toxicity profiles have now been identified, and our most promising compound is scheduled for clinical evaluation shortly. The biological evaluation of these compounds is being carried out by Professor Scott Franzblau and his team at the Institute for Tuberculosis Research, University of Illinois at Chicago. 
  • The success of Bedaquiline in targeting the oxidative phosphorylation metabolic pathway of the TB bacterium has resulted in the search for other inhibitors of this pathway. Several novel chemical classes of compounds which inhibit ATP synthesis have now been identified and our group has received further funding from GATB to optimise some of these and develop them further. The biological evaluation of these compounds is also being carried out by Professor Scott Franzblau and his team.
  • New potential enzyme drug targets within the TB bacterium continue to be identified. We have recently received funding from GATB to work on a medicinal chemistry program to develop inhibitors of a novel kinase target that is believed to be important in maintaining survival of the bacterium.

 

Global Alliance for TB Drug Development

Institute for TB Research, Chicago

Recent publications


  • Sutherland, H. S., Tong, A. S. T., Choi, P. J., Conole, D., Blaser, A., Franzblau, S. G., . . . Palmer, B. D. (2018). Structure-activity relationships for analogs of the tuberculosis drug bedaquiline with the naphthalene unit replaced by bicyclic heterocycles. Bioorganic & Medicinal Chemistry, 26(8), 1797-1809. doi:10.1016/j.bmc.2018.02.026
  • Tong, A. S., Choi, P. J., Blaser, A., Sutherland, H. S., Tsang, S. K., Guillemont, J., . . . Conole, D. (2017). 6-Cyano analogues of bedaquiline as less lipophilic and potentially safer diarylquinolines for tuberculosis. ACS Medicinal Chemistry Letters, 8(10), 1019-1024. doi:10.1021/acsmedchemlett.7b00196
  • Choi, P. J., Sutherland, H. S., Tong, A. S., Blaser, A., Franzblau, S. G., Cooper, C. B., . . Palmer, B. D. (2017). Synthesis and evaluation of analogues of the tuberculosis drug bedaquiline containing heterocyclic B-ring units. Bioorganic and Medicinal Chemistry Letters, 27(23), 5190-5196. doi:10.1016/j.bmcl.2017.10.042

Group members