2. Academic Validation
  3. SuFEx-based antitubercular compound irreversibly inhibits Pks13

SuFEx-based antitubercular compound irreversibly inhibits Pks13

  • Nature. 2025 Sep;645(8081):755-763. doi: 10.1038/s41586-025-09286-3.
Inna V Krieger # 1,  Paridhi Sukheja # 2,  Baiyuan Yang # 2,  Su Tang 1,  Daniel Selle 1,  Ashley Woods 2,  Curtis Engelhart 3,  Pradeep Kumar 4 5,  Michael B Harbut 2,  Dongdong Liu 2,  Brendan Tsuda 2,  Bo Qin 2,  Grant A L Bare 6,  Gencheng Li 6,  Victor Chi 2,  Julian Gambacurta 7,  Janine Hvizdos 7,  Matthew Reagan 7,  Isabelle L Jones 7,  Lisa M Massoudi 8,  Lisa K Woolhiser 8,  Alessandro Cascioferro 2,  Erica Kundrick 2,  Parul Singh 4 5,  William Reiley 7,  Thomas R Ioerger 9,  Dilipkumar Reddy Kandula 10,  Jacob W McCabe 10,  Taijie Guo 11,  David Alland 4 5,  Helena I Boshoff 12,  Dirk Schnappinger 3,  Gregory T Robertson 8,  Khisi Mdluli 13,  Kyoung-Jin Lee 2,  Jiajia Dong 11,  Shuangwei Li 2,  Peter G Schultz 2 14,  Sean B Joseph 2,  Melissa S Love 2,  K Barry Sharpless 6,  H Michael Petrassi 2,  Arnab K Chatterjee 2,  James C Sacchettini 15,  Case W McNamara 16
Affiliations

Affiliations

  • 1 Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA.
  • 2 Calibr-Skaggs Institute for Innovative Medicines, A Division of Scripps Research, La Jolla, CA, USA.
  • 3 Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA.
  • 4 New Jersey Medical School Division of Infectious Disease, Department of Medicine, Rutgers University, Newark, NJ, USA.
  • 5 Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University, Newark, NJ, USA.
  • 6 Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • 7 Trudeau Institute, Saranac Lake, NY, USA.
  • 8 Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA.
  • 9 Department of Computer Science, Texas A&M University, College Station, TX, USA.
  • 10 AB Sciex LLC, Framingham, MA, USA.
  • 11 Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 12 Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
  • 13 Gates Medical Research Institute, Cambridge, MA, USA.
  • 14 The Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.
  • 15 Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA. [email protected].
  • 16 Calibr-Skaggs Institute for Innovative Medicines, A Division of Scripps Research, La Jolla, CA, USA. [email protected].
  • # Contributed equally.
PMID: 40739353 DOI: 10.1038/s41586-025-09286-3
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.

Figures
Products