Mycobacterium tuberculosis (Mtb), causative agent of tuberculosis, is the deadliest bacterial pathogen. According to World Health Organization statistics, infections by Mtb are among the top 10 causes of death worldwide. In one of the most striking examples of a health disparity, it is well-known that the severity of the tuberculosis pandemic is highly correlated with wealth. The number of cases in high income nations are roughly 10 per 100,000; whereas in some economically countries the burden can exceed 400 per 100,000. Nevertheless, tuberculosis demands attention of all nations because it is highly contagious and Mtb is increasingly dangerous via its resistance to drugs. Mtb is the focus of drug-development programs and its intracellular proteases have emerged among the hottest drug targets in the past decade. A wealth of genetic data indicate that Mtb requires these enzymes for either viability or surviving insults from the immune response. Predictions that these enzymes are “druggable” are validated by a growing number of reports of bioactive small molecules that perturb their catalytic activity. There is cause for optimism in that these molecules could be “first-in-class” drugs that act either as bacteriocidals or suppressors of pathogenicity. This seminar will describe our efforts to gain mechanistic insights into and accelerate the medicinal development of small molecules that perturb the functions of the ClpP peptidase and the 20S proteasome in Mtb.

Development of drugs for the treatment of tuberculosis

2019 Spring National Meeting

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