Current perspectives on DprE1 inhibitors as antitubercular agents

Tuberculosis (TB) remains a leading cause of mortality worldwide, with the escalating prevalence of multidrugresistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains severely compromising the efficacy of conventionalfirst- and second-line therapies. This crisis necessitates the urgent development of anti-TB agents with novel mechanisms ofaction. Decaprenyl-phosphoryl-β-D-ribose 2′-oxidase (DprE1), an essential flavoenzyme in the mycobacterial cell wallarabinan polymerization pathway, has emerged as a highly promising and druggable target. This review provides acomprehensive analysis of the current landscape of DprE1 inhibitors, detailing their mechanism of action, the structuralbiology of the target, and the diverse chemical classes under development. We critically evaluate the progress of leadcandidates, including the covalent inhibitors BTZ-043 and macozinone (PBTZ169), and the non-covalent inhibitorsquabodepistat (OPC-167832) and TBA-7371, which have advanced to clinical trials. Recent breakthroughs in understandingthe DprE1-DprE2 complex structure and the discovery of novel scaffolds, such as selenium-based bioisosteres, arediscussed. The review synthesizes findings from preclinical and clinical studies, highlighting the challenges of resistance,pharmacokinetic optimization, and the potential role of these inhibitors in future, shorter TB treatment regimens.