メタロ-β-ラクタマーゼ (IMP-1) の非可逆的阻害剤の開発^*

抄録

Pathogenic bacteria that produce metallo-β-lactamases (MBLs) are emerging as a new threat to the medical community. These enzymes catalyze the hydrolysis of almost β-lactam antibiotics. Moreover, serine-β-lactamase inhibitors are ineffective against MBLs. Thus, the development of inhibitors for MBLs is important.
We prepared two inhibitors, pentafluorophenyl 3-mercaptopropionate (PFMP, 1) and 3- (3-mercaptopropionylsulfanyl) propionic acid pentafluorophenyl ester (MPAP, 2) for one of MBLs, IMP-1. From the gel-filtration experiment of the enzyme-inhibitor complex, these compounds inhibited IMP-1 irreversibly.
Moreover, X-ray crystallography revealed that inhibitor 2 covalently binds to IMP-1 to form an amide bond between the amino group (N^ζ) of Lys224 and the inhibitor.