Targeting de novo purine biosynthesis for tuberculosis treatment

• 成果类型: Article
• 署名作者: Lamprecht, Dirk A.; Wall, Richard J.; Leemans, Annelies; Truebody, Barry; Sprangers, Joke; Fiogbe, Patricia; Davies, Cadi; Wetzel, Jennefer; Daems, Stijn; Pearson, William; Pillay, Vanessa; Saylock, Samantha; Ricketts, M. Daniel; Davis, Ellie; Huff, Adam; Grell, Tsehai; Lin, Shiming; Gerber, Michelle; Vos, Ann; Dallow, John; Willcocks, Sam J.; Roubert, Christine; Sans, Stephanie; Desorme, Amandine; Chappat, Nicolas; Ray, Aurelie; Pereira Moraes, Mariana; Washington, Tracy; D'Erasmo, Hope; Sancheti, Pavankumar; Everaerts, Melissa; Monshouwer, Mario; Esquivias, Jorge; Larrouy-Maumus, Gerald; Draghia Akli, Ruxandra; Fletcher, Helen; Pym, Alexander S.; Aldridge, Bree B.; Sarathy, Jansy P.; Clancy, Kathleen W.; Stoops, Bart; Dhar, Neeraj; Steyn, Adrie J. C.; Jackson, Paul; Aguilar-Perez, Clara; Koul, Anil
• 署名单位: Johnson & Johnson; Johson & Johnson Belgium; Janssen Pharmaceuticals; University of London; London School of Hygiene & Tropical Medicine; Africa Health Research Institute; University of Kwazulu Natal; Johnson & Johnson; Johnson & Johnson USA; Janssen Biotech Inc; Janssen Pharmaceuticals; University of Saskatchewan; Johnson & Johnson; Johson & Johnson Belgium; Janssen Pharmaceuticals; Tufts University; Johnson & Johnson; Janssen Pharmaceuticals; Imperial College London; Johnson & Johnson; Janssen Pharmaceuticals; Tufts University; University of Alabama System; University of Alabama Birmingham; University of Alabama System; University of Alabama Birmingham; Johnson & Johnson; Janssen Pharmaceuticals; Johnson & Johnson USA; University of Cape Town; Brunel University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1967
• DOI: 10.1038/s41586-025-09177-7
• 发表日期: 2025-08-07
• 关键词: drug-resistant tuberculosis; gene-expression

摘要

Tuberculosis remains the leading cause of death from an infectious disease1,2. 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 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.