Structure-based discovery of metallo-type carbapenemase inhibitor and application to bacteriological examination

2014 Fiscal Year Final Research Report

• Project/Area Number: 24790570
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Laboratory medicine
• Research Institution: Nagoya University
• Principal Investigator: WACHINO Jun-ichi 名古屋大学, 医学(系)研究科(研究院), 助教 (00535651)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 薬剤耐性菌

Outline of Final Research Achievements

We determined the crystal structure of SMB-1 using 1.6A diffraction data, and revealed that the overall structure of SMB-1 was quite similar to those of the other subclass B3 MBLs, AIM-1, L1, and BJP-1. The electron density map corresponding to a water molecule (wat1), which is assumed to contribute as the attacking nucleophile on the carbonyl carbon of the beta-lactam ring, was observed. SMB-1 possesses a unique amino acid residue, Q157, which probably plays a role in recognition of beta-lactams via the hydrogen bond interaction. In addition, we determined the mercaptoacetate (MCR)-complexed SMB-1 structure and revealed that the mode of its inhibition by MCR: the thiolate group bridges to two zinc ions (Zn1 and Zn2), and occupy the space to which beta-lactams originally bind. Finally, we performed in silico screening to find effective inhibitors of SMB-1 and found four agents which could behave as inhibitors of SMB-1.

Free Research Field

病態検査学