Development of small molecules that work cooperatively with ciprofloxacin to clear salmonella biofilms in a chronic gallbladder carriage model

Abstract

Salmonella enterica serovars cause millions of infections each year that result either in typhoid fever or salmonellosis. Among those serovars that cause typhoid fever, Salmonella enterica subspecies Typhi can form biofilms on gallstones in the gallbladders of acutely-infected patients, leading to chronic carriage of the bacterium. These biofilms are recalcitrant to antibiotic-mediated eradication, leading to chronic fecal shedding of the bacteria, which results in further disease transmission. Herein, we report the synthesis and anti-biofilm activity of a 55-member library of small molecules based upon a previously identified hit that both inhibits and disrupts S. Typhi and S. Typhimurium (a nontyphoidal model serovar for S. Typhi) biofilms. Lead compounds inhibit S. Typhimurium biofilm formation in vitro at sub-micromolar concentrations, and disperse biofilms with five-fold greater potentency than the parent compound. Three of the most promising compounds demonstrated synergy with ciprofloxacin in a murine model of chronic Salmonella carriage. This work furthers the development of effective anti-biofilm agents as a promising therapeutic avenue for the eradication of typhoidal Salmonella.