An ongoing effort continues against the rising tide of antibiotic resistant bacteria, underscoring the urgent need to discover antibiotics with a novel mechanism of action. To this end, we have focused on the inhibition of the bacterial enzyme N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE). Guided by docking with the computational suite Molecular Operating Environment (MOE) and lead molecules obtained through a HiTS (High Throughput Screening) assay, several lead molecules and analogs were identified, synthesized, and optimized by our research group. These potential new inhibitors are tested in our recently described and updated biochemical DapE ninhydrin assay, with IC50 data obtained for inhibitors including cyclobutanone, tetrazole, pyrazole, N-aryl acyclic sulfonamide, and indoline sulfonamide analogs. Thus far, we have conducted our assay and obtained results utilizing the bacterial species H.influenzae and A.baumannii, working toward confirming broad spectrum antibiotic activity.

Novel antibiotic discovery by employing the DapE ninhydrin-based assay to evaluate DapE inhibitors

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