Research Projects

Tuberculosis (TB) is a major cause of death, causing approximately 1.5 million deaths annually. The bacterium, Mycobacterium tuberculosis, is responsible for the increase in drug resistance to existing anti-tubercular drugs like isoniazid or rifampicin. To combat this, novel antibiotics are needed that target new molecular targets and are widespread in M. tuberculosis. One potential target for TB treatment is the riboswitch-mediated regulation of M. tuberculosis metabolic pathways. Riboswitches, typically found in 5' untranslated regions (5'UTRs) of pathogenic bacterial mRNAs, recognize essential metabolites and undergo conformational changes to regulate genes involved in the synthesis or transport of the metabolite. Nearly seven riboswitch classes are identified in M. tuberculosis, and repression of these pathways through riboswitch targeting could be lethal. Research on targeting riboswitches for anti-tuberculosis drug development is mostly limited to bioinformatics studies, and no attempts have been made to develop riboswitch-targeting synthetic molecules for TB treatment. Experimental data has shown that targeting riboswitches in M. tuberculosis with synthetic analogues is a promising strategy for TB treatment. Some compounds displayed noticeable antitubercular activity with MIC99 in the range of 6.25 to 25 μM and tolerable cytotoxicity with IC50 of more than 25 μM. This study aims to use structure-based drug design to develop synthetic molecules targeting TPP, SAM-IV, c-di-AMP, and FMN riboswitches in M. tuberculosis based on their involvement in the synthesis of essential metabolites and the absence of alternative regulatory metabolic pathways for these metabolites.