ATP competitive inhibitors of d-alanine–d-alanine ligase based on protein kinase inhibitor scaffolds

d-Alanine–d-alanine ligase (DDl) is an essential enzyme in bacterial cell wall biosynthesis and an important target for developing new antibiotics. Here, we describe a new approach to identify new inhibitor scaffolds for DDl based on similarity in the ATP binding region of different kinases and DDl. After an initial screening of several protein kinase inhibitors, we found that the Brutons’s tyrosine kinase inhibitor LFM-A13, an analog of the Leflunomide metabolite A771726, inhibits DDl with a Ki of 185 μM. A series of malononitrilamide and salicylamide derivatives of LFM-A13 has been synthesized to confirm the validity of this scaffold as an inhibitor of DDl.

New inhibitors for d-alanine–d-alanine ligase can be found based on the similarity of the ATP binding site of kinases and d-alanine–d-alanine ligase.Figure optionsDownload as PowerPoint slide