Small Molecule Benzothiophene with Efficacy in a Mouse Model of Drug-Resistant Infection.

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 activity this class of bacteria, we noted that the benzothiophene JSF-2827 exhibited promising antibacterial activity against . 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 efficacy in an immunocompetent mouse model of acute, drug-resistant infection. The findings suggest a rationale for the further evolution of this promising series to afford a novel therapeutic strategy to treat drug-resistant infection.