Salmonella enterica serovars cause an estimated 93 million infections each year that result either in typhoid fever or salmonellosis. Among those subpecies 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 in 3-5% of patients. These biofilms are recalcitrant to antibiotic-mediated eradication, leading to chronic fecal shedding of the bacteria. As humans are the only known reservoir for this pathogen, this fecal shedding is responsible for the re-infection of poorly treated water supplies, and perpetuates the disease in endemic regions, specifically Sub-Saharan Africa and Southeast Asia. If gallstone-mediated biofilm formation can be prevented or disrupted, treatment and potential eradication of the disease becomes possible. Here, we report the synthesis and anti-biofilm activity of a library of small molecules based upon a previously identified hit that demonstrated the ability to both inhibit and disrupt S. Typhi and S. Typhimurium (a nontyphoidal model serovar for S. Typhi) biofilms. Lead compounds were identified that inhibit S. Typhimurium biofilm formation in vitro at sub-micromolar concentrations and are five-fold more potent at biofilm disruption than the parent compound. Three of the most promising compounds were further tested in a murine model of chronic Salmonella carriage, and demonstrated cooperativity with ciprofloxacin. The most potent biofilm disruptor resulted in a 4.5-5 log-fold reduction in bacteria in the gallbladder when dosed with 1mg/kg ciprofloxacin. Further in vivo testing with varying doses of ciprofloxacin and this novel anti-biofilm compound resulted in nearly undetectable levels of bacteria in the gallbladder and two distal organs, the liver and spleen, at the highest dose of ciprofloxacin (4mg/kg). This work furthers the development of effective anti-biofilm agents as a therapeutic against Salmonella chronic carriage.

Treatment of Salmonella enterica gallbladder-mediated biofilms: A structure activity relationship study examining the effect of anti-biofilm agents in a dual therapeutic approach with ciprofloxacin

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.