Assay Platform for Clinically Relevant Metallo-尾-lactamases

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• 作者：Sander S. van Berkel ; J眉rgen Brem ; Anna M. Rydzik ; Ramya Salimraj ; Ricky Cain ; Anil Verma ; Raymond J. Owens ; Colin W. G. Fishwick ; James Spencer ; Christopher J. Schofield
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September 12, 2013
• 年：2013
• 卷：56
• 期：17
• 页码：6945-6953
• 全文大小：391K
• 年卷期：v.56,no.17(September 12, 2013)
• ISSN：1520-4804

文摘

Metallo-尾-lactamases (MBLs) are a growing threat to the use of almost all clinically used 尾-lactam antibiotics. The identification of broad-spectrum MBL inhibitors is hampered by the lack of a suitable screening platform, consisting of appropriate substrates and a set of clinically relevant MBLs. We report procedures for the preparation of a set of clinically relevant metallo-尾-lactamases (i.e., NDM-1 (New Delhi MBL), IMP-1 (Imipenemase), SPM-1 (S茫o Paulo MBL), and VIM-2 (Verona integron-encoded MBL)) and the identification of suitable fluorogenic substrates (umbelliferone-derived cephalosporins). The fluorogenic substrates were compared to chromogenic substrates (CENTA, nitrocefin, and imipenem), showing improved sensitivity and kinetic parameters. The efficiency of the fluorogenic substrates was exemplified by inhibitor screening, identifying 4-chloroisoquinolinols as potential pan MBL inhibitors.