Human prostaglandin reductases dearomatize and inactivate benzothiazinone antitubercular drugs
Abstract Macozinone (MCZ, PBTZ169) is a potent clinical-stage benzothiazinone antitubercular agent that covalently inhibits the essential mycobacterial flavoenzyme DprE1. In some mammals, MCZ undergoes reductive dearomatization to H 2 MCZ, a Hydride Meisenheimer Complex, identified as the major circulating metabolite in humans. We demonstrate for the first time that the NADPH-dependent human prostaglandin reductases PTGR1 and PTGR2 catalyze MCZ dearomatization into H 2 MCZ, resulting in loss of antimycobacterial activity. This reaction represents a heretofore undescribed host-mediated metabolic inactivation pathway for a therapeutic agent. Although H 2 MCZ may constitute a transient reactive intermediate, ex vivo and cellular data indicate that it does not contribute to antimycobacterial activity in vivo. Pharmacological inhibition of PTGR1 and PTGR2 using diclofenac, indomethacin, dicumarol, or the selective inhibitor PTGR2-IN-1 suppresses H 2 MCZ formation and partially restores MCZ antimycobacterial activity in vitro. Together, these findings uncover a previously unrecognized noncanonical enzymatic mechanism of drug metabolism involving dearomatization in humans. Targeting prostaglandin reductases may represent a strategy to enhance benzothiazinone exposure and efficacy.
Authors
- Dany Spaggiari
- Neeraj Dhar (ORCID: https://orcid.org/0000-0002-5887-8137)
- Laurent Arthur Decosterd (ORCID: https://orcid.org/0000-0002-9840-1325)
- François Versace (ORCID: https://orcid.org/0000-0002-7262-7617)
- Emilyne Blattes
- Laura E. Rothuizen (ORCID: https://orcid.org/0000-0002-6836-7568)
- Benedetta Cena
- Lenka Laštovičková (ORCID: https://orcid.org/0000-0003-4070-4152)
- Anthony Vocat
- Amarande Murisier
- Haïthem Chtioui (ORCID: https://orcid.org/0000-0003-3821-6942)
- Andréanne Lupien (ORCID: https://orcid.org/0000-0002-4777-0497)
- Aimable Nahimana (ORCID: https://orcid.org/0000-0003-4968-3167)
- Sylvie Guinchard
- Carine Bardinet
- Paul Thoueille (ORCID: https://orcid.org/0000-0002-2305-4277)
- François R. Girardin (ORCID: https://orcid.org/0000-0002-0842-927X)
- Caroline Wagner (ORCID: https://orcid.org/0000-0003-4320-3433)
- Giuseppina Milano (ORCID: https://orcid.org/0000-0002-5560-4667)
- Axel Bellotti
- Myriam Briki (ORCID: https://orcid.org/0000-0001-6334-5565)
- Vladimı́r Wsól (ORCID: https://orcid.org/0000-0003-3745-7648)
- Thomas Mercier (ORCID: https://orcid.org/0000-0003-1921-4837)
- Stewart Thomas Cole (ORCID: https://orcid.org/0000-0003-1400-5585)
- Eva Choong (ORCID: https://orcid.org/0000-0001-6776-4978)
- Onya Opota (ORCID: https://orcid.org/0000-0002-5421-0607)
- Vincent Desfontaine (ORCID: https://orcid.org/0000-0002-2231-4946)
- Laurent Robert Chiarelli (ORCID: https://orcid.org/0000-0003-0348-9764)
- Thierry Buclin (ORCID: https://orcid.org/0000-0003-0639-5536)
- Benoit Guery (ORCID: https://orcid.org/0000-0002-6526-0714)
- Océane Corpataux
- Vadim Makarov
- Sarah Abou-Zite
- Michel A Duchosal
- Richa Mishra
- Raphaël Sommer
- Olga Riabova
Institutions
- Russian Academy of Sciences (RU)
- Charles University (CZ)
- University of Pavia (IT)
- Centre Hospitalier Universitaire Vaudois (CH)
- Federal Research Centre «Fundamentals of Biotechnology» of the Russian Academy of Sciences (RU)
- Innovative Medicines for Tuberculosis Foundation (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- University of Lausanne (CH)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2026-10-07
- DOI
- https://doi.org/10.1038/s44321-026-00526-1
- Primary Topic
- Pharmacogenetics and Drug Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00