2. Academic Validation
  3. Hit-to-Lead Optimization of Acetazolamide-Based Bacterial Carbonic Anhydrase Inhibitors with Efficacy In Vivo for Treatment of Vancomycin-Resistant Enterococci Septicemia

Hit-to-Lead Optimization of Acetazolamide-Based Bacterial Carbonic Anhydrase Inhibitors with Efficacy In Vivo for Treatment of Vancomycin-Resistant Enterococci Septicemia

  • J Med Chem. 2025 Sep 11;68(17):18597-18624. doi: 10.1021/acs.jmedchem.5c01584.
Katrina J Holly 1,  Prabhakara R Tharra 1,  Nader S Abutaleb 2 3,  Alessio Nocentini 4,  Ahmed A Abouelkhair 2 3,  Molly S Youse 1,  Anil Kumar Marapaka 1,  Abdallah S Abdelsattar 2 3,  Weiwei An 1,  Faith L Drummond 1,  Olivia C Snell 1,  Claudiu T Supuran 4,  Mohamed N Seleem 2 3,  Daniel P Flaherty 1 5 6
Affiliations

Affiliations

  • 1 Borch Department of Medicinal Chemistry and Molecular Pharmacology, West Lafayette, Indiana 47907, United States.
  • 2 Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, United States.
  • 3 Center for One Health Research, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, United States.
  • 4 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Firenze 50019, Italy.
  • 5 Purdue Institute for Drug Discovery, West Lafayette, Indiana 47907, United States.
  • 6 Purdue Institute of Inflammation, Immunology, and Infectious Disease, West Lafayette, Indiana 47907, United States.
PMID: 40878880 DOI: 10.1021/acs.jmedchem.5c01584
Abstract

As one of the leading causes of hospital-acquired infections reported by the National Healthcare Safety Network, vancomycin-resistant enterococci (VRE) continue to afflict patients in healthcare facilities, with limited FDA-approved drugs available for treating systemic infections. Our group previously showed the 1,3,4-thiadiazole acetazolamide human Carbonic Anhydrase Inhibitor scaffold can be repositioned with potent in vitro efficacy against enterococcal pathogens. However, only acetazolamide has been explored for in vivo efficacy in murine septicemia models. Herein, we report a hit-to-lead account in which we expand the structure-activity relationship for the 1,3,4-thiadiazole scaffold, identified lead candidates with favorable in vitro ADME profiles, and advanced a promising lead analog forward into in vivo pharmacokinetic studies. Ultimately, we demonstrated efficacy in a murine septicemic peritonitis Infection model after oral dosing. Overall, we demonstrate a successful example of an acetazolamide-based lead compound with in vivo therapeutic potential for the treatment of septicemic vancomycin-resistant VRE Infection.

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