Resistance is futile: Pathogenic bacteria that produce metallo‐β‐lactamases are recognized as a serious threat because of their resistance to antibiotics. The title compound has now been shown to be an irreversible inhibitor for a metallo‐β‐lactamase (IMP‐1). The X‐ray crystallographic structure (see picture) has revealed that the inhibitor binds to IMP‐1 with formation of a covalent amide bond with the amino group (Nζ) of Lys 224.

Widerstand ist sinnlos: Pathogene Bakterien, die Metallo‐β‐lactamasen produzieren, gelten wegen ihrer Resistenz gegen Antibiotika als große Gefahr. Nun wurde die Titelverbindung als irreversibler Inhibitor einer Metallo‐β‐lactamase (IMP‐1) identifiziert. Laut den Befunden der Röntgenstrukturanalyse (siehe Bild) bindet der Inhibitor an IMP‐1 unter Bildung einer kovalenten Amidbindung mit der Aminogruppe (Nζ) von Lys 224.

IMP-2, a subclass B1 metallo-β-lactamase (MBL), is a Zn(II)-: Classes A, C, and D are serine enzymes that use a serine residue as a nucleophile, whereas class B consists of metallo enzymes whose active sites contain one or two Zn(II) ion(s) and are referred to as metallo-β-lactamases (MBLs). MBLs are divided into three subclasses (B1, B2, B3) based on the sequence of the Zn(II) ligands.3) MBLs hydrolyze most β-lactams used currently, such as cephems and carbapenems, but not monobactam such as aztreonam. MBLs are hardly blocked by the inhibitors for serine β-lactamases, including clavulanate, sulbactam and, tazobactam.In 1994, IMP-1 MBL, belonging to subclass B1, was first identified from Serratia marcescens and Pseudomonas aeruginosa in Japan. 4,5) Its gene, bla IMP , encodes the IMP-1 enzyme and is integrated as a gene cassette into integrons carried by transferable plasmids. 6) Therefore, the bla IMP gene can spread among different nosocomial pathogens horizontally. To date, at least 48 variants of IMP-type MBLs have been deposited (http://www.lahey.org/Studies) by the end of July 2014.In 1997, an IMP-2 MBL was identified from an Acinetobacter baumannii clinical isolate AC-54/97 in Italy, 7) followed by the isolation of IMP-2-producing A. baumannii, A. lowffii, and P. aeruginosa in Japan.8) The IMP-2 gene (bla IMP-2 ) is also carried as an integron-bone gene cassette, similar to the IMP-1 gene (bla IMP ). 6,7) IMP-2 possesses approximately an 85% amino acid identity with IMP-1, and differs in 36 amino acids from IMP-1: 10 amino acid residues are clustered within the signal peptide region and the remaining 26 amino acid residues are found in the mature protein 7) (Fig. 2C). The structure of IMP-1 suggests that 4 of 26 amino acid residues predicted to be involved in substrate recognition in IMP-2 (Ser68, Gln198, Asp227, and Ser261; the amino acid residues of IMP-1 and IMP-2 are designated by their BBL number 3) ) are located in the neighborhood at its active site within a distance of ca. 9 Å (Fig. 1). The remaining 22 amino acid residues are located at the protein surface or are far from the active site.The kinetic parameters of the hydrolysis of several β-lactams by IMP-2 are overall similar to those by IMP-1, but the catalytic efficiency values of the two enzymes (k cat /K m ) for ampicillin are different for IMP-1 and 0.21 µM −1 s −1 for IMP-2.7) The k cat /K m value of IMP-1 to IMP-2 increases 23-fold, so IMP-1 hydrolyses ampicillin more efficiently than IMP-2. These differences in kinetic parameters might be related to the subtle structural changes arising from the different amino acid sequences of the enzymes, even though the 6 amino acid residues (His116, His118, Asp120, His196, Cys221, and His263) which construct the active site of the enzyme are conserved between IMP-1 and IMP-2.Therefore, determination of the fine three-dimensional