Targeting de novo purine biosynthesis for tuberculosis treatment

Tuberculosis remains the leading cause of death from an infectious disease, responsible for 1.3 million deaths annually. Here, we report the discovery of a first-in-class small molecule inhibitor targeting PurF, the first enzyme in the mycobacterial de novo purine biosynthesis pathway. Our lead candidate, JNJ-6640, exhibited nanomolar bactericidal activity in vitro. Using an array of comprehensive genetic and biochemical approaches, we confirmed JNJ-6640 was highly selective for mycobacterial PurF compared to the human homologue. Single-cell level timelapse microscopy demonstrated PurF inhibition leads to a downstream impact on DNA replication. Proof-of-concept studies using a long-acting injectable formulation demonstrated the compound's in vivo efficacy. Finally, we show inclusion of JNJ-6640 could play a crucial role in improving the current treatment regimen for drug-resistant TB. Taken together, we demonstrate that JNJ-6640 is a promising chemical lead and show that targeting purine metabolism is a novel strategy for TB drug development.