2. Academic Validation
  3. Small Molecule Benzothiophene with In Vivo Efficacy in a Mouse Model of Drug-Resistant Enterococcus faecium Infection

Small Molecule Benzothiophene with In Vivo Efficacy in a Mouse Model of Drug-Resistant Enterococcus faecium Infection

  • J Med Chem. 2024 Jan 25;67(2):1384-1392. doi: 10.1021/acs.jmedchem.3c01846.
Ricardo Gallardo-Macias 1,  Riccardo Russo 2,  Matthew Sherwood 1,  Mark Jaskowski 1,  Wissam Nasser 1,  Pankaj Sharma 1,  Margareta Tuckman 2,  Eric Singleton 2,  Hsin Pin Ho 3,  Steven Park 3,  Jimmy S Patel 1,  Amir George 1,  David Perlin 3,  Matthew D Zimmerman 3,  Nancy Connell 2,  Joel S Freundlich 1 2
Affiliations

Affiliations

  • 1 Department of Pharmacology, Physiology, and Neuroscience, Rutgers University─New Jersey Medical School, Newark, New Jersey 07103, United States.
  • 2 Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenço Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University─New Jersey Medical School, Newark 07103, New Jersey, United States.
  • 3 Public Health Research Institute, Rutgers University─New Jersey Medical School, Newark, New Jersey 07103, United States.
PMID: 38225186 DOI: 10.1021/acs.jmedchem.3c01846
Abstract

Hospital-acquired infections, caused by ESKAPE bacteria, are a challenging global public health concern, in part due to the emergence of drug-resistant strains. While profiling a diverse set of compounds for in vitro activity versus this class of bacteria, we noted that the benzothiophene JSF-2827 exhibited promising Antibacterial activity against Enterococcus faecium. A hit evolution campaign ensued, involving the design, synthesis, and biological assay of analogues designed to address early issues such as a short mouse liver microsome half-life and a modest mouse pharmacokinetic profile. Among these derivatives, JSF-3269 was found to exhibit an enhanced profile and in vivo efficacy in an immunocompetent mouse model of acute, drug-resistant E. faecium Infection. The findings suggest a rationale for the further evolution of this promising series to afford a novel therapeutic strategy to treat drug-resistant E. faecium Infection.

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