Targeting de novo purine biosynthesis for tuberculosis treatment
Tuberculosis remains the leading cause of death from an infectious disease<sup>1,2</sup>. 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.
Authors
- Alexander S. Pym (ORCID: https://orcid.org/0000-0002-6260-8180)
- Neeraj Dhar (ORCID: https://orcid.org/0000-0002-5887-8137)
- Sam Willcocks (ORCID: https://orcid.org/0000-0002-0756-4859)
- Bart Stoops (ORCID: https://orcid.org/0000-0002-1092-2696)
- Richard J. Wall (ORCID: https://orcid.org/0000-0003-3487-3187)
- M. Daniel Ricketts
- William H. Pearson (ORCID: https://orcid.org/0000-0003-4146-9422)
- Gerald J Larrouy-Maumus (ORCID: https://orcid.org/0000-0001-6614-8698)
- Jorge Esquivias (ORCID: https://orcid.org/0000-0001-6050-5092)
- Paul Jackson
- Stéphanie Sans (ORCID: https://orcid.org/0000-0003-3077-4536)
- Alexander Leemans (ORCID: https://orcid.org/0000-0002-9306-6126)
- Tsehai A.J. Grell (ORCID: https://orcid.org/0000-0001-8578-7559)
- Barry Truebody (ORCID: https://orcid.org/0000-0001-7066-3916)
- Nicolas Chappat
- Adam Huff
- Helen A. Fletcher (ORCID: https://orcid.org/0000-0002-0435-1006)
- Bree B. Aldridge (ORCID: https://orcid.org/0000-0003-2236-1424)
- Clara Aguilar-Pérez (ORCID: https://orcid.org/0000-0001-7438-9141)
- Jansy Passiflora Sarathy (ORCID: https://orcid.org/0000-0002-1532-146X)
- Ruxandra Draghia‐Akli (ORCID: https://orcid.org/0000-0001-6372-4039)
- Adrie J. C. Steyn (ORCID: https://orcid.org/0000-0001-9177-8827)
- Mario Monshouwer (ORCID: https://orcid.org/0000-0001-9605-4692)
- Dirk A. Lamprecht (ORCID: https://orcid.org/0000-0003-1066-9026)
- Ann Vos (ORCID: https://orcid.org/0000-0001-9018-5878)
- Aurélie Ray
- Kathleen W. Clancy (ORCID: https://orcid.org/0000-0003-0425-2689)
- Shi‐Ming Lin (ORCID: https://orcid.org/0000-0002-7048-6734)
- V.L. Pillay
- Stijn Daems
- Pavankumar Sancheti
- Joke Sprangers
- Patricia Fiogbe
- Samantha Saylock
- Amandine Desorme
- Melissa Everaerts
- John Dallow
- Ellie Davis
- Cadi Davies
- J. Denise Wetzel
- Anil Koul
- Mariana Pereira Moraes (ORCID: https://orcid.org/0009-0004-0962-2620)
- Tracy Washington (ORCID: https://orcid.org/0000-0003-2679-688X)
- Michelle Gerber
- Hope D’Erasmo
Institutions
- Tufts University (US)
- Charles River Laboratories (Netherlands) (NL)
- Janssen (Belgium) (BE)
- University of Cape Town (ZA)
- University of Alabama at Birmingham (US)
- University of Saskatchewan (CA)
- London School of Hygiene & Tropical Medicine (GB)
- Novavax (United States) (US)
- Janssen (United Kingdom) (GB)
- Charles River Laboratories (United States) (US)
- Africa Health Research Institute (ZA)
- Hackensack Meridian Health (US)
- Janssen (United States) (US)
- Center for Discovery (US)
- Imperial College London (GB)
- Brunel University of London (GB)
- University of KwaZulu-Natal (ZA)
Publication Details
- Journal
- Nature
- Published
- 2025-06-18
- DOI
- https://doi.org/10.1038/s41586-025-09177-7
- Citations
- 15
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 20.94