SuFEx-based antitubercular compound irreversibly inhibits Pks13

Inna V. Krieger, Paridhi Sukheja, Baiyuan Yang, Su Tang, Daniel Selle, Ashley Woods, Curtis Engelhart, Pradeep Kumar, Michael B. Harbut, Dongdong Liu, Brendan Tsuda, Bo Qin, Grant A. L. Bare, Gencheng Li, Victor Chi, Julian Gambacurta, Janine Hvizdos, Matthew Reagan, Isabelle L. Jones, Lisa M. Massoudi, Lisa K. Woolhiser, Alessandro Cascioferro, Erica Kundrick, Parul Singh, William Reiley, Thomas R. Ioerger, Dilipkumar Reddy Kandula, Jacob W. McCabe, Taijie Guo, David Alland, Helena I. Boshoff, Dirk Schnappinger, Gregory T. Robertson, Khisi Mdluli, Kyoung-Jin Lee, Jiajia Dong, Shuangwei Li, Peter G. Schultz, Sean B. Joseph, Melissa S. Love, K. Barry Sharpless, H. Michael Petrassi, Arnab K. Chatterjee, James C. Sacchettini () and Case W. McNamara ()
Additional contact information
Inna V. Krieger: Texas A&M University
Paridhi Sukheja: A Division of Scripps Research
Baiyuan Yang: A Division of Scripps Research
Su Tang: Texas A&M University
Daniel Selle: Texas A&M University
Ashley Woods: A Division of Scripps Research
Curtis Engelhart: Weill Cornell Medicine
Pradeep Kumar: Rutgers University
Michael B. Harbut: A Division of Scripps Research
Dongdong Liu: A Division of Scripps Research
Brendan Tsuda: A Division of Scripps Research
Bo Qin: A Division of Scripps Research
Grant A. L. Bare: The Scripps Research Institute
Gencheng Li: The Scripps Research Institute
Victor Chi: A Division of Scripps Research
Julian Gambacurta: Trudeau Institute
Janine Hvizdos: Trudeau Institute
Matthew Reagan: Trudeau Institute
Isabelle L. Jones: Trudeau Institute
Lisa M. Massoudi: Colorado State University
Lisa K. Woolhiser: Colorado State University
Alessandro Cascioferro: A Division of Scripps Research
Erica Kundrick: A Division of Scripps Research
Parul Singh: Rutgers University
William Reiley: Trudeau Institute
Thomas R. Ioerger: Texas A&M University
Dilipkumar Reddy Kandula: AB Sciex LLC
Jacob W. McCabe: AB Sciex LLC
Taijie Guo: Shanghai Jiao Tong University
David Alland: Rutgers University
Helena I. Boshoff: National Institutes of Health (NIH)
Dirk Schnappinger: Weill Cornell Medicine
Gregory T. Robertson: Colorado State University
Khisi Mdluli: Gates Medical Research Institute
Kyoung-Jin Lee: A Division of Scripps Research
Jiajia Dong: Shanghai Jiao Tong University
Shuangwei Li: A Division of Scripps Research
Peter G. Schultz: A Division of Scripps Research
Sean B. Joseph: A Division of Scripps Research
Melissa S. Love: A Division of Scripps Research
K. Barry Sharpless: The Scripps Research Institute
H. Michael Petrassi: A Division of Scripps Research
Arnab K. Chatterjee: A Division of Scripps Research
James C. Sacchettini: Texas A&M University
Case W. McNamara: A Division of Scripps Research

Nature, 2025, vol. 645, issue 8081, 755-763

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09286-3

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