The bacterium Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever – infecting and killing an estimated 21 million and 200,000 individuals each year, respectively. Individuals contract the disease by consuming food or water contaminated with the etiologic agent S. Typhi. Typhoid fever is characterized by high fever, abdominal pain, bacteremia, headache, diarrhea, and malaise.

The Need

S. Typhi will persist in the gallbladder of 3-5% of individuals, after resolution of the acute infection, through an asymptomatic chronic carrier state, during which fecal shedding allows the bacteria to spread. Patients remain unknowingly infectious, a particularly dangerous cycle in areas without developed sewage treatment and sanitation procedures. In this chronic carrier state, S. Typhi forms biofilms – organized, multicellular communities encapsulated in an extracellular matrix of polysaccharides, proteins, and extracellular DNA – on gallstones. The biofilm extracellular matrix protects the bacteria from antibiotics, host immune responses, and other environmental threats. As such, compounds that are effective against biofilms are critical for resolving these issues.

The Technology

This technology describes a compound, M4, that was found to display significant biofilm dispersal and inhibition of biofilm formation in S. Typhi. M4 was initially identified among a group of 8 compounds that were found to display similar, albeit less strong, activity. M4 shows promising activity with inhibition of biofilm formation (EC₅₀ of 8 µM) and biofilm dispersion (EC₅₀ of 20 µM). M4 has shown efficacy in a mouse model of chronic typhoid fever. Co-administration of M4 (10 mg/kg/day) with ciprofloxacin (sub-MIC dose) reduced the gallbladder bacterial burden by 3-4.5 logs and prevented bacterial dissemination to peripheral organs.

Commercial Applications

This technology can be used for treating chronic carriers of typhoid fever and future work in biofilm dispersal and inhibition.

Benefits/Advantages

The identified compound M4 has the potential as a pharmaceutical treatment to eliminate Salmonella biofilms in asymptomatic chronic carriers following typhoid fever, which could dramatically reduce the incidence and spread of typhoid fever globally.

Patents

Patent applications pending in China and the United States.