Human prostaglandin reductases dearomatize and inactivate benzothiazinone antitubercular drugs.
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Briki Myriam, Wagner Caroline A, Desfontaine Vincent, Vocat Anthony, Opota Onya, Abou-Zite Sarah, Corpataux Océane, Cena Benedetta, Guinchard Sylvie, Versace François, Murisier Amarande, Mercier Thomas, Blattes Emilyne, Bardinet Carine, Thoueille Paul, Wsol Vladimir, Lastovickova Lenka, Chtioui Haithem, Rothuizen Laura E, Nahimana Aimable, Bellotti Axel, Chiarelli Laurent R, Spaggiari Dany, Dhar Neeraj, Mishra Richa, Sommer Raphaël, Lupien Andréanne, Duchosal Michel A, Guery Benoît, Girardin François R, Milano Giuseppina, Riabova Olga, Makarov Vadim, Buclin Thierry, Cole Stewart T, Choong Eva, Decosterd Laurent A
Аннотация
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 H2MCZ, 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 H2MCZ, resulting in loss of antimycobacterial activity. This reaction represents a heretofore undescribed host-mediated metabolic inactivation pathway for a therapeutic agent. Although H2MCZ 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 H2MCZ 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.