Targeting de novo purine biosynthesis for tuberculosis treatment PMID: 40533558

ADC Targets in Oncology

2026-04-10

Targeting de novo purine biosynthesis for tuberculosis treatment

Nature. 2025 Aug;644(8075):214-220. doi: 10.1038/s41586-025-09177-7.

Dirk A Lamprecht ^# ¹ ² , Richard J Wall ^# ³ , Annelies Leemans ^# ⁴ , Barry Truebody ⁵ , Joke Sprangers ⁴ ⁶ , Patricia Fiogbe ⁴ ⁶ , Cadi Davies ³ , Jennefer Wetzel ⁴ , Stijn Daems ⁴ , William Pearson ³ , Vanessa Pillay ⁵ , Samantha Saylock ⁷ , M Daniel Ricketts ⁷ , Ellie Davis ³ , Adam Huff ⁷ , Tsehai Grell ⁷ , Shiming Lin ⁸ , Michelle Gerber ⁸ , Ann Vos ⁹ , John Dallow ³ , Sam J Willcocks ³ ¹⁰ , Christine Roubert ¹¹ , Stéphanie Sans ¹¹ , Amandine Desorme ¹¹ , Nicolas Chappat ¹¹ , Aurélie Ray ¹¹ , Mariana Pereira Moraes ¹² , Tracy Washington ¹² , Hope D'Erasmo ¹² , Pavankumar Sancheti ⁹ , Melissa Everaerts ⁹ , Mario Monshouwer ⁴ , Jorge Esquivias ¹³ , Gerald Larrouy-Maumus ¹⁴ , Ruxandra Draghia Akli ⁷ ¹⁵ , Helen Fletcher ³ ¹⁶ , Alexander S Pym ¹⁶ , Bree B Aldridge ¹² ¹⁷ , Jansy P Sarathy ¹⁸ , Kathleen W Clancy ⁷ , Bart Stoops ⁹ , Neeraj Dhar ⁸ , Adrie J C Steyn ⁵ ¹⁹ ²⁰ , Paul Jackson ²¹ , Clara Aguilar-Pérez ⁴ , Anil Koul ²² ²³

Affiliations

1. Janssen Global Public Health, LLC, Janssen Pharmaceutica NV, Antwerp, Belgium. [email protected].
2. Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa. [email protected].
3. Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.
4. Janssen Global Public Health, LLC, Janssen Pharmaceutica NV, Antwerp, Belgium.
5. Africa Health Research Institute, University of KwaZulu Natal, Durban, South Africa.
6. Charles River Laboratories, Antwerp, Belgium.
7. Janssen Research and Development, LLC, Janssen Pharmaceutica, Spring House, PA, USA.
8. Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
9. Janssen Research and Development, LLC, Janssen Pharmaceutica NV, Antwerp, Belgium.
10. Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University of London, Uxbridge, UK.
11. Evotec ID (LYON) SAS, Lyon, France.
12. Department of Molecular Biology and Microbiology, Tufts University School of Medicine and Stuart B. Levy Center for Integrated Management of Antimicrobial Resistance, Boston, MA, USA.
13. Janssen Research and Development, LLC, Janssen Pharmaceutica, Toledo, Spain.
14. Centre for Bacterial Resistance Biology, Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London, UK.
15. Research and Development, Novavax, Inc., Gaithersburg, MD, USA.
16. Janssen Global Public Health, LLC, Janssen Pharmaceutica, High Wycombe, UK.
17. Department of Biomedical Engineering, Tufts University School of Engineering, Medford, MA, USA.
18. Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA.
19. Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA.
20. Centers for AIDS Research and Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
21. Janssen Global Public Health, LLC, Janssen Pharmaceutica, La Jolla, CA, USA.
22. Janssen Global Public Health, LLC, Janssen Pharmaceutica NV, Antwerp, Belgium. [email protected].
23. Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK. [email protected].
# Contributed equally.

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 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.