Targeting de novo purine biosynthesis for tuberculosis treatment.

ABSTRACT: Tuberculosis remains the leading cause of death from an infectious disease^1,2. 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 demonstrat

SUBMITTER: Lamprecht DA 

PROVIDER: S-EPMC12328218 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature