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
  • 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.

Products