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

Ricardo Gallardo-Macias, Riccardo Russo, Matthew Sherwood, Mark Jaskowski, Wissam Nasser, Pankaj Sharma, Margareta Tuckman, Eric Singleton, Hsin Pin Ho, Steven Park, Jimmy S. Patel, Amir George, David Perlin, Matthew D. Zimmerman, Nancy Connell, Joel S. Freundlich

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1384-1392
Number of pages9
JournalJournal of medicinal chemistry
Volume67
Issue number2
DOIs
StatePublished - Jan 25 2024
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2024 American Chemical Society

PubMed: MeSH publication types

  • Journal Article

Fingerprint

Dive into the research topics of 'Small Molecule Benzothiophene with In Vivo Efficacy in a Mouse Model of Drug-Resistant Enterococcus faecium Infection'. Together they form a unique fingerprint.

Cite this