Small Molecule Benzothiophene with In Vivo Efficacy in a Mouse Model of Drug-Resistant Enterococcus faecium Infection.
Ricardo Gallardo-MaciasRiccardo RussoMatthew SherwoodMark JaskowskiWissam NasserPankaj SharmaMargareta TuckmanEric SingletonHsin Pin HoSteven ParkJimmy S PatelAmir GeorgeDavid PerlinMatthew D ZimmermanNancy ConnellJoel S FreundlichPublished in: Journal of medicinal chemistry (2024)
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.
Keyphrases
- drug resistant
- multidrug resistant
- mouse model
- acinetobacter baumannii
- public health
- small molecule
- escherichia coli
- healthcare
- biofilm formation
- liver failure
- high throughput
- staphylococcus aureus
- pseudomonas aeruginosa
- cystic fibrosis
- emergency department
- respiratory failure
- structure activity relationship
- drug induced
- adverse drug
- extracorporeal membrane oxygenation
- acute respiratory distress syndrome