The most widely used DapE assay monitors amide bond cleavage of the L,L-SDAP substrate spectrophotometrically at 225 nm. This assay is simple and reliable for simple inhibitors, but it cannot be used to test potential inhibitors that absorb strongly in the UV region, precluding its use in testing many of the preferred medicinal chemistry leads and analogs. Ninhydrin-based assays provide ease of application and reliability to detect primary amino groups such as that formed upon the hydrolysis of L,L-SDAP. We synthesized N 6 -methylated and N 6 -acetylated L,L-SDAP derivatives to prevent ninhydrin side reactions in the assay and also tested them as viable substrates for the Haemophilus influenza DapE (HiDapE) used in the assay. The data showed that the N-methylated derivative was both less reactive with ninhydrin and also was a better suited substrate for the HiDapE. In addition to the development of the assay itself we have also used a high throughput coupled screening to identify a number of lead HiTS that show binding potential to DapE. These compounds will be tested as inhibitors themselves, while also being the basis for potential derivatives. The synthesis of these derivatives will be guided by structure activity relationships (SAR) as well as Lipinski’s rule of five, a general guide for predicting orally activity of potential drugs.

Spectrophotometric assay for dapE-encoded N-succinyl-L,L-di aminopimelic acid desuccinylase: Potential antibiotic target

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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