An Open Science, Medicinal Chemistry Program to Develop New Therapeutics Against Non-Tuberculous Mycobacteria

Non-tuberculous mycobacteria (NTM) cause opportunistic infections in immunosuppressed patients and those with structural lung diseases, such as cystic fibrosis. Prevalence of NTM infections is increasing worldwide, but current treatments are inadequate.1 We have established an open science, structure-based drug discovery program to develop new diaminopyrimidine-based inhibitors of a well-established drug target, dihydrofolate reductase (DHFR) from two of the most predominant NTM in the clinic - M. avium (Mav) and M. abscessus (Mab). Our current best compound, a derivative of P218 shown below,2 is potent in biochemical assays (IC50 of 0.3 nM and 1.4 nM for Mav and Mab DHFR, respectively) and active against Mav in culture (MIC50 ~300 nM). We are currently working on improving compound selectivity against the human enzyme (only 2 to 8-fold) and the in vivo stability of the molecule, as its ether-based linker is prone to metabolism.