“Structure-activity Relationship Studies of Small Molecules Directed Against the T-box

High rates of antibiotic use have resulted in the pervasiveness of multi-drug resistant organisms. With rising drug-resistance the development of antibiotics with new targets against these pathogens is imperative. The T-box regulatory mechanism is a process specific to Grampositive bacteria and controls many essential genes including aaRS genes, which are code for the aminoacyl-tRNA synthetases required to charge tRNA. The T-box Specifier Loop is a novel target for antibacterial drug discovery as we hypothesize that a small compound bound to the Specifier Loop will inhibit transcription of essential bacterial genes resulting in bacterial cell death or growth arrest. We used an in silico drug discovery approach combined with structureactivity relationship studies (SAR) to evaluate small molecules as potential putative antibiotics directed against Gram-positive bacteria. SAR studies have been used to determine important structural elements of the initial hit compounds so that a compound with optimal activity and Gram-positive selectivity can be developed into an antimicrobial agent.