4-Amino-2-Sulfanylbenzoic Acid as a Potent Subclass B3 Metallo-β-Lactamase-Specific Inhibitor Applicable for Distinguishing Metallo-β-Lactamase Subclasses.

摘要: The number of cases infection with carbapenem-resistant Enterobacteriaceae (CRE) has been increasing and become a major clinical public health concern. Production metallo-β-lactamases (MBLs) is one the principal carbapenem resistance mechanisms in CRE. Therefore, developing MBL inhibitors promising strategy to overcome problems conferred by MBLs. To date, development evaluation have focused on subclass B1 MBLs but not B3 In present study, we searched for (specifically, SMB-1) found thiosalicylic acid (TSA) be potent inhibitor SMB-1 (50% inhibitory concentration [IC50], 0.95 μM). TSA inhibited purified considerable degree was active against Escherichia coli cells producing SMB-1, as meropenem (MEM) MIC producer only slightly reduced TSA. We then introduced primary amine synthesized 4-amino-2-sulfanylbenzoic (ASB), which substantially MEM MICs producers. X-ray crystallographic analyses revealed that ASB binds two zinc ions, Ser221, Thr223 at site SMB-1. These are ubiquitously conserved residues across clinically relevant also significantly other MBLs, including AIM-1, LMB-1, L1. characterization provides starting point optimum inhibitors.