The Need

Non-typhoidal salmonellosis is one of the most significant food-borne diseases, in the United States and globally. There are no vaccines available for human use to prevent this disease, and only broad-spectrum antibiotics available to treat the disease. However, antibiotic resistance is on the rise and novel therapeutics are needed.

The Technology

Researchers at The Ohio State University, led by Dr. Brian Ahmer, discovered a Salmonella locus, whose mutation causes extreme attenuation of fitness in mice. This locus includes the Salmonella fraB gene and mutations in fraB cause an accumulation of the FraB substrate that is toxic to Salmonella. This led to an issued patent covering the method of selecting an agent that inhibits the expression or function of the fra locus of Salmonella, including inhibition of FraB.

Additionally, the inventors have discovered small molecule inhibitors of FraB through high-throughput screening using growth-based assays. 224,000 compounds were screened, and several compounds were found that inhibit Salmonella in a fra-dependent manner with IC₅₀ values of 89-150 µM. Some were found to be uncompetitive inhibitors of FraB with Ki' values from 26-116 µM. Hit compounds are undergoing modification and further investigation.

A main benefit, this pathway is found in no animals and only a few bacteria, thus targeting FraB with novel antimicrobials is expected to leave the normal microbiota intact and have little or no effect on the host.

Commercial Applications

• Salmonellosis therapeutics

Benefits/Advantages

• Salmonella-specific narrow-spectrum treatment
• Can limit the side effects caused by disruption of normal microbiota
• Avoids selecting for microbial resistance among the normal microbiota
• Can target Salmonella resistant to traditional antibiotics

Publications

• Sabag-Daigle, A. et al. Identification of Small-Molecule Inhibitors of the Salmonella FraB Deglycase Using a Live-Cell Assay. Microbiology Spectrum, 2023, e04606-22.
• Thirugnanasambantham, P. et al. Serendipitous Discovery of a Competitive Inhibitor of FraB, a Salmonella Deglycase and Drug Target. Pathogens, 2022, 11(10):1102.
• Sabag-Daigle, A. et al. A metabolic intermediate of the fructose-asparagine utilization pathway inhibits growth of a Salmonella fraB mutant. Scientific Reports, 2016, 6:28117.
• Sabag-Daigle, A. et al. Use of Attenuated but Metabolically Competent Salmonella as a Probiotic To Prevent or Treat Salmonella Infection. Infection and Immunity, 2016, 84(7):2131-2140
• Ali, M. M. et al. Fructose-Asparagine Is a Primary Nutrient during Growth of Salmonella in the Inflamed Intestine. PLOS Pathogens, 2014, 10(6):e1004209.

Patents

• Compounds for Treating Infections, patent pending.
• Methods for the identification, characterization, and use of inhibitors of the fructose-asparagine utilization pathway. United States, issued 2020.