Structure-guided discovery of novel dUTPase inhibitors with anti- Nocardia activity by computational design.

The zoonosis caused by Nocardia is increasing seriously. But commonly used antibiotic drugs often lead to resistance. N. seriolae dUTPase ( Ns dUTPase) plays a key role in the proliferation of Nocardia , and was regarded as a potent drug target. However, there was little report about the Ns dUTPase inhibitors. In this study, we discovered a series of novel Ns dUTPase inhibitors to fight against Nocardia . The first crystal structure of Ns dUTPase was released, and a structure-based computational design was performed. Compounds 4b and 12b exhibited promising activities towards Ns dUTPase (IC ₅₀  = 0.99 μM and 0.7 μM). In addition, they showed satisfied anti- Nocardia activity (MIC value ranges from 0.5 to 2 mg/L) and low cytotoxicity, which were better than approved drugs oxytetracycline and florfenicol. Molecular modelling study indicated that hydrophobic interaction might be the main contribution for ligand binding. Our results suggested that Ns dUTPase inhibitors might be a useful way to repress Nocardia .