Riboflavin biosynthetic pathway: A potent antitubercular drug target

Tuberculosis (TB) is one of the leading causes of death, according to the World Health Organization report a total of 1.5 million people died from TB in 2020 and its the second leading infectious killer after COVID-19 (above HIV/AIDS). TB is caused from a Mycobacterium tuberculosis (M. tuberculosis) bacterium. The increase in M. tuberculosis drug resistance to existing anti-tubercular drugs, such as isoniazid or rifampicin is the major challenge for TB treatment. Thus, to overcome the drug resistance challenge there is urgent need for development of novel antibiotics that employ new molecular targets. One potentially vulnerable target for antibiotics is the riboswitch-mediated regulation of bacterial metabolic pathways. Riboswitches are RNA gene regulatory elements and are involved in biochemical pathways regulation that are essential for bacterial survival as well as virulence, thus repression of these pathways through riboswitch targeting could be lethal. M. tuberculosis strictly depends on the endogenous biosynthesis of riboflavin because of the lack of riboflavin transporter. Riboflavin (vitamin B2) is the direct precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are crucial enzyme cofactors required for variety of redox reactions, catalyze oxidization and hydroxylation. Thus, endogenous riboflavin biosynthesis pathway is a promising target for the development of novel antimycobacterial drugs. In this study we have demonstrated that targeting FMN riboswitches is promising strategy for antimycobacterial therapy. We have synthesized structurally similar analogues of riboflavin library and screened against M. tuberculosis H37Rv strain. We observed that certain compounds displayed noticeable antitubercular activity with MIC99 in the range of 6.25 to 25 μM and tolerable cytotoxicity with IC50 of more than 100 μM. These findings suggest that systematic alterations around these leads through iterative synthesis and docking could gradually lead to identification of more potent antitubercular drugs that can target the FMN riboswitches.
For more details,
Harale B, Kidwai S, Ojha D, Singh M, Chouhan D, Singh R, Khedkar V, Rode AB* (2021) Synthesis and evaluation of antimycobacterial activity of riboflavin derivatives. Bioorg Med Chem Lett. 48, 128236.
https://www.sciencedirect.com/science/article/pii/S0960894X21004637