期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 28, 期 6, 页码 1037-1042出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2018.02.025
关键词
Natural product; Rosmarinic acid; Salvianolic acid; Metallo-beta-lactamases; Target identification
资金
- National Natural Science Foundation of China [81502989]
- Scientific Research Foundation of Sichuan University [20822041A4193]
Rosmarinic acid (RA), a polyphenolic phytochemical, has broad-spectrum biological and pharmacological activity. A virtual target screening method termed IFPTarget combined with enzyme inhibition assays led to the identification of the clinically relevant metallo-beta-lactamase (MBL) VIM-2 as one of unexploited targets of RA. The enzyme kinetic studies indicated that RA is a fully reversible, substrate-competitive VIM-2 inhibitor. The isothermal titration calorimetry (ITC) analyses revealed that the initial binding of RA to VIM-2 is mainly due to enthalpy contribution. Further inhibition assays with RA related compounds revealed that salvianolic acid A, a derivative of RA, manifests potent inhibition to VIM-2, more interestingly, which shows inhibitory activity against the NDM-1, another clinically relevant MBL subtype, and the serine-beta-lactamase TEM-1 that is structurally and mechanistically distinct from the VIM-2 and NDM-1. (C) 2018 Elsevier Ltd. All rights reserved.
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