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, Nicolas Chappat, Aurélie Ray, Mariana Pereira Moraes, Tracy Washington, Hope D’Erasmo, Pavankumar Sancheti, Melissa Everaerts, Mario Monshouwer, Jorge Esquivias, Gerald Larrouy-Maumus, Ruxandra Draghia Akli, Helen Fletcher, Alexander S. Pym, Bree B. Aldridge, Jansy P. Sarathy, Kathleen W. Clancy, Bart Stoops, Neeraj Dhar, Adrie J. C. Steyn, Paul Jackson, Clara Aguilar-Pérez and Anil Koul ()
Additional contact information
Dirk A. Lamprecht: Janssen Pharmaceutica NV
Richard J. Wall: London School of Hygiene and Tropical Medicine
Annelies Leemans: Janssen Pharmaceutica NV
Barry Truebody: University of KwaZulu Natal
Joke Sprangers: Janssen Pharmaceutica NV
Patricia Fiogbe: Janssen Pharmaceutica NV
Cadi Davies: London School of Hygiene and Tropical Medicine
Jennefer Wetzel: Janssen Pharmaceutica NV
Stijn Daems: Janssen Pharmaceutica NV
William Pearson: London School of Hygiene and Tropical Medicine
Vanessa Pillay: University of KwaZulu Natal
Samantha Saylock: Janssen Pharmaceutica
M. Daniel Ricketts: Janssen Pharmaceutica
Ellie Davis: London School of Hygiene and Tropical Medicine
Adam Huff: Janssen Pharmaceutica
Tsehai Grell: Janssen Pharmaceutica
Shiming Lin: University of Saskatchewan
Michelle Gerber: University of Saskatchewan
Ann Vos: Janssen Pharmaceutica NV
John Dallow: London School of Hygiene and Tropical Medicine
Sam J. Willcocks: London School of Hygiene and Tropical Medicine
Christine Roubert: Evotec ID (LYON) SAS
Stéphanie Sans: Evotec ID (LYON) SAS
Amandine Desorme: Evotec ID (LYON) SAS
Nicolas Chappat: Evotec ID (LYON) SAS
Aurélie Ray: Evotec ID (LYON) SAS
Mariana Pereira Moraes: Tufts University School of Medicine and Stuart B. Levy Center for Integrated Management of Antimicrobial Resistance
Tracy Washington: Tufts University School of Medicine and Stuart B. Levy Center for Integrated Management of Antimicrobial Resistance
Hope D’Erasmo: Tufts University School of Medicine and Stuart B. Levy Center for Integrated Management of Antimicrobial Resistance
Pavankumar Sancheti: Janssen Pharmaceutica NV
Melissa Everaerts: Janssen Pharmaceutica NV
Mario Monshouwer: Janssen Pharmaceutica NV
Jorge Esquivias: Janssen Pharmaceutica
Gerald Larrouy-Maumus: Imperial College London
Ruxandra Draghia Akli: Janssen Pharmaceutica
Helen Fletcher: London School of Hygiene and Tropical Medicine
Alexander S. Pym: Janssen Pharmaceutica
Bree B. Aldridge: Tufts University School of Medicine and Stuart B. Levy Center for Integrated Management of Antimicrobial Resistance
Jansy P. Sarathy: Hackensack Meridian Health
Kathleen W. Clancy: Janssen Pharmaceutica
Bart Stoops: Janssen Pharmaceutica NV
Neeraj Dhar: University of Saskatchewan
Adrie J. C. Steyn: University of KwaZulu Natal
Paul Jackson: Janssen Pharmaceutica
Clara Aguilar-Pérez: Janssen Pharmaceutica NV
Anil Koul: Janssen Pharmaceutica NV

Nature, 2025, vol. 644, issue 8075, 214-220

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09177-7

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