Pyrazole-Based Inhibitors of the Bacterial Enzyme DapE as Potential Antibiotics

As bacteria become increasingly resistant to antibiotics, there is a need for new antibiotics using alternative pathways. To answer this need, our research investigates inhibitors of the bacterial enzyme N-succinyl-L,L-2,6-diaminopimelic acid desuccinylase (DapE). Based on previous work, we focused on pyrazole-based inhibitors, which were tested using a ninhydrin-based assay. The most potent pyrazole analog, 7d, has an IC50 of 17.9 ± 8.0 µM, and analog (R)-7q is a competitive inhibitor with an IC50 of 18.8 µM. A thermal shift assay demonstrated stabilization of the enzyme after binding with inhibitor (R)-7q and a Ki of 17.3 ± 2.8 µM.