Helmy Project

University Of Kentucky, Lexington KY

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY – PROJECT 9 (HELMY) Salmonella is the leading cause of bacterial foodborne illnesses with significant public health implications worldwide. Poultry is the main source and reservoir of human infections. Treating poultry with antibiotics is a common strategy to prevent Salmonella outbreaks in humans and vaccines are not effective at reducing foodborne illnesses. Antibiotics are also required to treat severe illnesses associated with Salmonella infections in humans. As a consequence, the emergence of antibiotic-resistant Salmonella has become an emerging concern. Additionally, untreated Salmonella infections have been linked to various chronic health issues such as colon and gallbladder cancers associated with Salmonella Typhi and Enteritidis, respectively. Therefore, there is a critical need for antibiotic alternatives to control infections in poultry and to mitigate the risk of Salmonella foodborne illness outbreaks, antimicrobial resistance, and cancer in humans. Quorum sensing plays a critical role in the survival, pathogenicity, virulence, biofilm formation, motility, and antibiotic production of several bacteria including Salmonella. Therefore, inhibition of QS using QS inhibitors (QSI) is an attractive “antibiotic- free” strategy to eradicate or limit Salmonella infections, thereby preventing the transmission to humans and the associated diseases due to acute and chronic infection. Since QSIs do not interfere with the metabolic processes of the bacteria, they will not exert selection pressure on the bacteria during treatment. Thus bacteria are less likely to develop resistance to QSIs. Through the screening of 1,900 compounds to identify the QS/AI-2 inhibitors against Salmonella Typhimurium, we identified 6 structurally diverse compounds that inhibited the QS/AI-2 production of Salmonella Typhimurium (≥95%; at 10 µM final concentration) without affecting bacterial growth. We compared their efficacy to the benchmark QSIs identified in previous studies and found that our compounds are >10-fold more potent than the benchmark comparators. We hypothesize that selective QSIs will show high efficacy in vitro, and in vivo and will open the door to identifying potential novel antimicrobial strategies. In this proposal, we will identify and evaluate the efficacy of the selected QSIs in vitro (Aim 1), evaluate the efficacy of the lead QSIs in the reservoir animal host (chickens, Aim 2), and identify the QSI target(s) of the selected leads (Aim 3). Completion of these aims will contribute to our long-term objective of developing new anti-Salmonella therapeutics that control the emergence of antibiotic-resistant Salmonella associated with poultry production and thus mitigate the risk of food illnesses and gallbladder and colon cancers in humans. CTCB mentorship and research support cores will facilitate this project in several key ways. Specifically, the Bio Core will continue to support the Aim 1 screening effort to advance hit prioritization and for new targets identified (Aim 3), engage on subsequent target-based screens. For priority hits, probe optimization and SAR will be conducted by the Chem Core. This will also be augmented by a CTCB mentorship team with extensive expertise in the gut microbiome, bacteriology, infectious disease, and pharmaceutical science.