Targeting de novo purine biosynthesis for tuberculosis treatment.

Abstract:

Tuberculosis remains the leading cause of death from an infectious disease. 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. The lead candidate, JNJ-6640, exhibited nanomolar bactericidal activity in vitro. Comprehensive genetic and biochemical approaches confirmed that JNJ-6640 was highly selective for mycobacterial PurF. Single-cell-level microscopy demonstrated a downstream effect on DNA replication. We determined the physiologically relevant concentrations of nucleobases in human and mouse lung tissue, showing that these levels were insufficient to salvage PurF inhibition. Indeed, proof-of-concept studies using a long-acting injectable formulation demonstrated the in vivo efficacy of the compound. Finally, we show that inclusion of JNJ-6640 could have a crucial role in improving current treatment regimens for drug-resistant tuberculosis. Together, we demonstrate that JNJ-6640 is a promising chemical lead and that targeting de novo purine biosynthesis represents a novel strategy for tuberculosis drug development.