Grant: Project Grant

Mycobacterium tuberculosis (Mtb) cause serious infectious disease such as TB, that kills nearly 2 million people annually. Mycobacterial infections are notoriously resistant to the existing antibiotics and often require combination of 3 or more antibiotics to eradicate. This underscores the need for new drug development. In this research work, we plan to develop a potent antibacterial compound against Mtb. This compound will be based on fenoxacrin, an antimicrobial we have identified in an earlier screen of compounds library against Mtb and other bacterial infections. Fenoxacrim showed potent activity against both drug-susceptible and drug-resistant clinical isolates of Mtb as well as high selectivity to the pathogens over mammalian cells making it suitable for further development. To understand the structural features required for its antibacterial potency and selectivity over mammalian cells, we synthesized different analogues of fenoxacrim and figured out the part of its chemical structure that could be modified to improve potency and selectivity. As such, more analogues with much enhanced potency and selectivity were generated. Preliminary work we conducted to study the mode of action of fenoxacrim showed it targets a key bacterial specific enzyme required to synthesize cell wall, known as undecaprenyl pyrophosphate synthase enzyme (UPPS). Notably, UPPS is a novel target that is not targeted by any of existing clinically approved antibacterials. The main aim of this research project is to advance fenoxacrim and its synthetic analogues by (i) further modifying its chemical structure to make a new drug candidate that is more potent, safe and suitable for oral administration, (ii) to conduct further studies to confirm UPPS as a target and study the detailed mode of action (iii) assess toxicity and efficacy of the best candidate in animal infection models. The ultimate outcome will be generation of a new drug candidate ready for clinical use.