Structure-Activity Relationship Analysis and hERG Liability Assessment of Second-Generation Antibiofilm Compounds...

Typhoid fever is a life-threatening illness caused by Salmonella enterica subspecies enterica serovar Typhi. The organ most implicated in chronic carriage and host transmission is the gallbladder due to bacterial biofilm formation on gallstones. Biofilms facilitate chronic infection because bacteria in biofilms are less susceptible to antibiotic treatment and immune factors in comparison to their planktonic brethren. Previously, we reported compounds that disrupt biofilms of Salmonella enterica serovar Typhimurium, a serovar closely related to S. Typhi, both in vitro and in vivo. This work extends the development of Salmonella antibiofilm agents through the further exploration of the parent scaffold. Lead antibiofilm compounds were tested for human ether-a-go-go-related gene (hERG) channel inhibition, from which we report new lead compounds with improved antibiofilm activity and reduced hERG channel inhibition.