THE SYNTHESIS OF NOVEL AGENTS TARGETING SALMONELLA ENTERICA TYPHIMURIUM
The Ohio State University
Foodborne illness resulting from non-typhoidal Salmonella enterica is a major contributor to global diarrheal diseases , with the potential to induce life-threatening morbidity within afflicted patients. In addition to its widespread impact, S. enterica has developed significant antimicrobial resistance, challenging the efficacy of current antibiotics. Through high-throughput screening (HTS), a promising hit compound was identified as an inhibitor of a unique Fructose-Asparagine (F-Asn) metabolic pathway utilized by S. enterica. This pathway converts F-Asn into Glucose-6-Phosphate (G6P) through a multi-step pathway involving several enzymes, including FraB . Inhibiting FraB leads to cell death due to the accumulation of a toxic intermediate, 6-Phosphofructose-Aspartate (6-P-F-Asp). Building upon the original hit scaffold, an extensive exploration of structure-activity relationships (SAR) has been undertaken in an attempt to enhance the potency of the original hit and create a novel narrow-spectrum antibiotic. The original hit offers a multitude of functionality that can be easily modified to explore the SAR, which allowed for the synthesis of 26 unique derivatives. While the SAR panel may not have yielded significantly more potent compounds, ongoing HTS efforts explore alternative chemical cores to effectively inhibit this crucial metabolic pathway.
Narrow-spectrum, medicinal chemistry, Salmonella enterica, antiboitics