Orientin mediates protection against MRSA-induced pneumonia by inhibiting Sortase A.

Drug-resistant pathogenic () has severely threatened human health and arouses widespread concern. Sortase A (SrtA) is an essential virulence factor of , which is responsible for the covalent anchoring of a variety of virulence-related proteins to the cell wall. SrtA has always been regarded as an ideal pharmacological target against infections. In this research, we have determined that orientin, a natural compound isolated from various medicinal plants, can effectively inhibit the activity of SrtA with an IC of 50.44 ± 0.51 µM. We further demonstrated that orientin inhibited the binding of to fibrinogen and diminished biofilm formation and the attaching of Staphylococcal protein A (SpA) to the cell wall . Using the fluorescence quenching assay, we demonstrated a direct interaction between orientin and SrtA. Further mechanistic studies revealed that the residues Glu-105, Thr-93, and Cys-184 were the key sites for the binding of SrtA to orientin. Importantly, we demonstrated that treatment with orientin attenuated virulence of and protected mice against -induced lethal pneumonia. These findings indicate that orientin is a potential drug to counter infections and limit the development of drug resistance.