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 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

SUBMITTER: Laurent, A Decosterd 

PROVIDER: S-SCDT-10_1038-S44321-026-00526-1 | biostudies-other |

REPOSITORIES: biostudies-other