Lysine and meso-diaminopimelic acid are essential precursors in the production of bacterial cell walls and require the activity of the enzyme N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE).1 Inhibition of DapE thus provides an opportunity to develop new antibiotics with a new mechanism of action, and since mammals obtain lysine through their diet, there is no comparable enzymatic pathway in mammals, and inhibitors of DapE are expected to show toxicity towards bacteria without mechanism-related toxicity in humans.2,3 A high-throughput screen of a random library of ca. 40,000 compounds against DapE was performed, which afforded new structures exhibiting significant inhibition of the enzyme, including indoline sulfonamide derivatives. Analogs have been synthesized to optimize inhibition of DapE, aided by molecular docking models alongside traditional medicinal chemistry methods to improve and guide inhibitor design. Progress in the synthesis and SAR of new inhibitors of DapE within this structural class of inhibitors will be described.References:1. Gillner, D. M.; Becker, D. P.; Holz, R. C. Lysine biosynthesis in bacteria: a metallodesuccinylase as a potential antimicrobial target. JBIC, J. Biol. Inorg. Chem. 2013  , 18, 155-163.2. Gillner, D.; Armoush, N.; Holz, R. C.; Becker, D. P. Inhibitors of bacterial N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) and demonstration of in vitro antimicrobial activity. Bioorg. Med. Chem. Lett. 2009  , 19, 6350-6352.3. Nocek, B. P.; Gillner, D. M.; Fan, Y.; Holz, R. C.; Joachimiak, A. Structural Basis for Catalysis by the Mono- and Dimetalated Forms of the dapE-Encoded N-succinyl-L,L-Diaminopimelic Acid Desuccinylase. J. Mol. Biol. 2010  , 397, 617-626.

Design and synthesis of inhibitors of the dimetalloprotease DapE as novel broad-spectrum antibiotics

248th National Meeting (2014)

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