Fragment-based drug discovery of potent and selective CYP121 inhibitors for tuberculosis

Tuberculosis is a re-emerging global epidemic which causes the death of more than 1.3 million people annually. Rising levels of antibiotic resistant bacterial strains and co-infection with HIV are key factors driving the resurgence of tuberculosis cases in developed countries, while inadequate hygiene and poor access to health care continue hinder disease control in developing nations. Current treatment regimens for tuberculosis require the co-administration of a cocktail of between 2-10 drugs over a 6-24 month period. The drugs cause numerous toxic side-effects, are difficult to administer and are incompatible with antiretroviral therapies for HIV and other co-morbid diseases. Consequently, patient compliance with treatment is low, further accelerating the development of antibiotic resistance. In addition, the only vaccine available for tuberculosis is ineffective in preventing the most common form of the disease in adults. As such, there is dire need for new drugs, with novel mechanisms of action. This talk will introduce the concepts of fragment-based drug discovery using my PhD research on developing inhibitors for the enzymes CYP121 and CYP144 as examples. The inhibitors developed through this research have the potential to be novel treatments for drug-resistant tuberculosis and also enable us to further investigate the biological systems which contribute to the pathogenicity and virulence of the causal bacterium Mycobacterium tuberculosis.