靶向新嘌呤生物合成治疗肺结核，这一成果由杨森全球公共卫生Anil Koul团队经过不懈努力而取得。2025年6月18日出版的《自然》发表了这项成果。

在这里，研究小组报道了一种针对PurF的小分子抑制剂的发现，PurF是分枝杆菌新生嘌呤生物合成途径中的第一个酶。主要候选物JNJ-6640在体外表现出纳摩尔杀菌活性。综合遗传和生化方法证实JNJ-6640对分枝杆菌PurF具有高选择性。单细胞水平显微镜显示了对DNA复制的下游效应。课题组人员测定了人类和非主题动物肺组织中核碱基的生理相关浓度，表明这些水平不足以挽救PurF抑制。事实上，关于长效注射制剂的概念验证研究证明了该化合物的体内功效。最后，该课题组研究人员表明，JNJ-6640的融合可能在改善当前耐药结核病的治疗方案中发挥关键作用。总之，该课题组人员证明JNJ-6640是一种很有前途的化学先导物，靶向嘌呤新生生物合成代表了结核病药物开发的新策略。

研究人员表示，结核病仍然是传染病导致死亡的主要原因。

附：英文原文

Title: Targeting de novo purine biosynthesis for tuberculosis treatment

Author: 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, Stphanie, Desorme, Amandine, Chappat, Nicolas, Ray, Aurlie, Pereira Moraes, Mariana, Washington, Tracy, DErasmo, 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-Prez, Clara, Koul, Anil

Issue&Volume: 2025-06-18

Abstract: 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.

DOI: 10.1038/s41586-025-09177-7

Source: https://www.nature.com/articles/s41586-025-09177-7