Title | SuFEx-based antitubercular compound irreversibly inhibits Pks13. |
Publication Type | Journal Article |
Year of Publication | 2025 |
Authors | Krieger IV, Sukheja P, Yang B, Tang S, Selle D, Woods A, Engelhart C, Kumar P, Harbut MB, Liu D, Tsuda B, Qin B, Bare GAL, Li G, Chi V, Gambacurta J, Hvizdos J, Reagan M, Jones IL, Massoudi LM, Woolhiser LK, Cascioferro A, Kundrick E, Singh P, Reiley W, Ioerger TR, Kandula DReddy, McCabe JW, Guo T, Alland D, Boshoff HI, Schnappinger D, Robertson GT, Mdluli K, Lee K-J, Dong J, Li S, Schultz PG, Joseph SB, Love MS, K Sharpless B, H Petrassi M, Chatterjee AK, Sacchettini JC, McNamara CW |
Journal | Nature |
Date Published | 2025 Jul 30 |
ISSN | 1476-4687 |
Abstract | Mycobacterium tuberculosis (Mtb) remains the world's deadliest bacterial pathogen1. There is an urgent medical need to develop new drugs that shorten the treatment duration to combat widespread multi-drug-resistant and extensive-drug-resistant Mtb. Here, we present a preclinical covalent compound, CMX410, that contains an aryl fluorosulfate (SuFEx)2 warhead and uniquely targets the acyltransferase domain of Pks13, an essential enzyme in cell-wall biosynthesis. CMX410 is equipotent against drug-sensitive and drug-resistant strains of Mtb and efficacious in multiple mouse models of infection. Inhibition by CMX410 is irreversible through a previously undescribed mechanism: CMX410 reacts with the catalytic serine of the AT domain of Pks13, rapidly and irreversibly disabling the active site by forming a β-lactam. CMX410 is highly selective for its target and thus demonstrates excellent pharmacological and safety profiles, including no adverse effects in a 14-day rat toxicity study up to 1,000 mg kg-1 per day. The distinctive mode of action from current drugs, high potency across all tested clinical isolates, oral bioavailability, favourable performance in drug combination testing and superior pharmacological and safety characteristics make CMX410 a promising first-in-class candidate to replace outdated cell-wall biosynthesis inhibitors, such as isoniazid and ethambutol, in tuberculosis regimens. |
DOI | 10.1038/s41586-025-09286-3 |
Alternate Journal | Nature |
PubMed ID | 40739353 |
PubMed Central ID | 3659392 |
Submitted by ljc4002 on August 21, 2025 - 1:41pm