Design, Synthesis, and Evaluation of Small Molecules as Potential Inhibitors of Bacterial Cell Wall Biosynthesis

Since the use of penicillin during World War II, the cell wall biosynthesis pathway has been a target for antibiotic treatment. Although hundreds of Ìāü-lactam antibiotics have been developed and studied at great length, bacterial resistance continually threatens the efficacy with which bacterial infections may be treated. This work investigates small molecule scaffolds as potential inhibitors of the cell wall biosynthesis pathway. The molecules are based on a dipeptide core or were discovered via computational screening of a small molecule library against the active site of a penicillin-binding protein. The small molecules were analyzed for in vivo antibacterial activity utilizing minimum inhibitory concentration determination. In vitro activity was evaluated using established nitrocefin and Bocillin-FL competition assays for DD-transpeptidases. Additionally, an Amplex Red coupled assay was employed to probe DD-carboxypeptidase activity. The design, synthesis, and evaluation of these small molecules are discussed herein.