One-third of the world's population is infected with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). The majority of these individuals have asymptomatic latent infections, which are the major reservoir for this pathogen. Also, frontline anti-TB drugs have only poor efficacy against latent TB. Therefore, identifying new drug targets for latent TB is integral to any strategy for TB eradication. The serine hydrolases represent a promising but understudied family of potential novel targets. This study will (1) profile serine hydrolase activity and (2) test the therapeutic potential of inhibiting serne hydrolases, both during active growth and non-replicating latency. We anticipate that the results of this study will aid the identification of targets important for mycobacterial survival during latency and provide therapeutic leads that can be optimized for clinical use against TB.
In 2011, an estimated 1.4 million people died from tuberculosis (TB), which is caused by Mycobacterium tuberculosis, making it the deadliest bacterial infection worldwide. Existing therapies have poor efficacy against all forms of the infection. Therefore, there is an urgent need for new drug targets to be developed. The goal of this proposal is to identify serine hydrolases as potential novel drug targets for antimicrobial therapy by profiling these enzymes in M. tuberculosis under conditions relevant to infection. Positive results from this study will support the inhibition of serine hydrolases in M. tuberculosi as a therapeutic strategy in the treatment of tuberculosis.