2026-03-17 インペリアル・カレッジ・ロンドン（ICL）
＜関連情報＞
- https://www.imperial.ac.uk/news/articles/2026/scientists-find-promising-drug-target-for-tuberculosis/
- https://www.nature.com/articles/s41586-025-09177-7#citeas
結核治療における新規プリン生合成の標的化 Targeting de novo purine biosynthesis for tuberculosis treatment
Dirk A. Lamprecht,Richard J. Wall,Annelies Leemans,Barry Truebody,Joke Sprangers,Patricia Fiogbe,Cadi Davies,Jennefer Wetzel,Stijn Daems,William Pearson,Vanessa Pillay,Samantha Saylock,M. Daniel Ricketts,Ellie Davis,Adam Huff,Tsehai Grell,Shiming Lin,Michelle Gerber,Ann Vos,John Dallow,Sam J. Willcocks,Christine Roubert,Stéphanie Sans,Amandine Desorme,…
Anil Koul
Nature Published:18 June 2025
DOI:https://doi.org/10.1038/s41586-025-09177-7
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.
