The misuse and overprescribing of antibiotics has caused a dramatic increase in multidrug resistant bacteria, hindering the effectiveness of many current marketed antibiotics. Bacterial drug resistance is rapidly becoming a global threat. A way to combat rising antibiotic resistance is to develop novel inhibitory compounds targeting an established enzyme essential to bacterial survival. Our research is focused on the bacterial enzyme, <i>N</i>-succinyl-L,L-diaminopimelic acid desuccinylase (DapE). DapE is found within the lysine biosynthetic pathway of all Gram negative and most Gram positive species of bacteria. DapE catalyzes a reaction that yields a precursor for the synthesis of m-DAP and lysine, which are necessary for bacterial cell wall synthesis, making it an attractive target. Due to the absence of the lysine biosynthetic pathway in mammals, DapE inhibitors are expected to exhibit high selectivity for bacteria, eliminating mechanism-based toxicity in humans. A high-throughput screening (HiTS) of a compound library with DapE was performed to identify candidates that could act as potential DapE inhibitors. This project focuses on the tetrazole thioether derivatives based on the HiTS-derived lead molecule. Optimization of this lead consisted of three point modifications defining the structure activity relationships, guided by molecular docking. These newly synthesized inhibitors are tested using our ninhydrin-based enzymatic assay to determine DapE inhibitory potency. A diverse library of novel inhibitors with improved potency against DapE will be described.

Design and synthesis of tetrazole derivatives as inhibitors of the bacterial enzyme N-succinyl-L,L,-2,6-diaminopimelic acid desuccinylase (DapE)

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.