Small Molecules that inhibit/disperse Salmonella biofilms & active in combination w/ciprofloxacin
Tech ID: 21-037
Inventors: Dr. Christian Melander, Dr. Kathryn Woolard
Date added: April 29, 2021
Molecules that are active in vitro and in vivo against Salmonella.
Asymptomatic carriers of Salmonella Typhi can accumulate Salmonella biofilms within the gallbladder of humans (Salmonella Typhi) and live-stock (Salmonella Typhimurium). This can result in a large number of bacteria excreted in feces and typhoid fever cases. Globally, typhoid fever has 14 million new infections and 136,000 fatalities each year. While the use of fluoroquinolone antibiotics such as ciprofloxacin resolve the majority of acute typhoid infections, it is estimated that 3–5% of acutely infected individuals will develop a chronic infection and continue to harbor S. Typhi after symptoms have subsided. Such asymptomatic chronic carriage presents a major public health problem in endemic regions, as carriers unknowingly serve as a reservoir for typhoidal serovars and remain capable of spreading the disease via fecal contamination. The asymptomatic carriage of S. Typhi is facilitated by the formation of biofilms on gallstones that protect the bacteria from the immune system and antibiotic drugs. This resistance makes antibiotics less likely to stop the growth of bacteria (bacteriostatic) as well as kill existing planktonic or biofilm bacterial phenotypes (bactericidal). As a result, antibiotics on their own are unable to breakdown and properly disperse biofilms. Current treatments have been semi-effective to break down gallstone biofilms, however, this results in the dissemination of planktonic bacterial phenotypes to peripheral organs, which is associated with increased mortality. While cholecystectomy has been shown to eliminate carriage, it is costly, invasive, and thus impractical to be widely adopted in affected regions. Because of the importance of biofilms in chronic carriage, the use of anti-biofilm agents is a promising strategy to eliminate gallbladder carriage and subsequently reduce the spread of typhoid fever.
Researchers at the University of Notre Dame in collaboration with the Nationwide Children’s Hospital have recently proposed small molecules that can be used synergistically with Ciprofloxacin to increase antibiotic effectiveness. In vivo experiments have shown that these compounds, when combined with Ciprofloxacin, reduced colony forming units in the gallbladder and reduced bacterial dissemination into peripheral organs. This novel approach is capable of both inhibiting Salmonella biofilm growth and disrupting pre-formed biofilm structures without affecting bacterial viability. The dual-therapy approach with Ciprofloxacin is a better alternative to existing antibiotics for Salmonella because it is a more effective anti-biofilm and causes significantly less planktonic bacterial phenotypes in the peripheral organs following gallstone biofilm breakdown. This treatment has potential to be used for Salmonella infections, biofilms formed on medical devices, and circulate throughout the body combatting biofilms in other locations throughout the body.
• Significant reduction of bacterial burden in the gallbladder and liver, more efficient than Ciprofloxacin alone
• Significant reduction in the amount of planktonic S. Typhi that is able to disseminate to peripheral organs.
• Global Antibiotic Market: $44B, 8.1% CAGR
• Ciprofloxacin Global Market: $1.97B
A dual-therapy approach for the treatment of biofilm-mediated Salmonella gallbladder carriage. PLoS Pathog. 2020, 16(12): e1009192
Technology Readiness Status
TRL3 - Experimental Proof of Concept