Antibiotic Resistance: Mono‐ and Dinuclear Zinc Complexes as Metallo‐β‐Lactamase Mimics

Abstract

Biomimetic systems containing one or two zinc(II) ions supported by phenolate ligands were developed as functional mimics of metallo-beta-lactamase. These complexes were shown to catalytically hydrolyze beta-lactam substrates, such as oxacillin and penicillin G. The dinuclear zinc complex 1, which has a coordinated water molecule, exhibits high beta-lactamase activity, whereas the dinuclear zinc complex 2, which has no water molecules, but labile chloride ligands, shows a much lower activity. The high beta-lactamase activity of complex 1 can be ascribed to the presence of a zinc-bound water molecule that is activated by being hydrogen bonded to acetate substituents. The kinetics of the hydrolysis of oxacillin by complex 1 and the effect of pH on the reaction rates are reported in detail. In addition, the kinetic parameters obtained for the synthetic analogues are compared with those of the natural metallo-beta-lactamase from Bacillus cereus (BcII). To understand the role of the second metal ion in hydrolysis, the syntheses and catalytic activities of two mononuclear complexes (3 and 4) that include coordinated water molecules are described. Interestingly, the mononuclear zinc complexes 3 and 4 also exhibit high activity, supporting the assumption that the second zinc ion is not crucial for the beta-lactamase activity.

Synthesis and structural characterization of Pd(II) complexes containing 2,6-bis[(dimethylamino)methyl]-4-methylphenolate ligand

“…The steric and electronic nature of this aminophenolate ligand can readily be changed to fine tune the property of its complex, which is often used as a catalyst for reactions such as ring-opening metathesis polymerization of 2-norbornene [2], lactide polymerization [3] and the hydrolysis of b-lactam substrates [4]. van Koten and co-workers reported vanadium complexes of 1 which are catalysts for the polymerization of a-olefins [5].…”

Spectroscopic and mechanistic studies of dinuclear metallohydrolases and their biomimetic complexes

“…31,90,112 Numerous research groups have reported Zn(II)Zn(II) hydrolase mimics. [14][15][16]18,20,22,90,92,101,[122][123][124][125][126][127] Bringing two Zn(II) ions in 132 The bidentate-bridging binding mode of the diphenyl phosphate was also proposed in solution using 31 P-NMR measurements because of the rather large shifts observed for the phosphate ester signal. 132 The separation of the two zinc centres in the biomimetics has been shown to be important.…”

Structural studies on New Delhi Metallo-β-lactamase (NDM-2) suggest old β-lactam, penicillin to be better antibiotic for NDM-2-harbouringAcinetobacter baumanni

“…Amino acid residues involved in the active site of the NDM-2 were found to be: (Figure 3). Metallo-β-lactamases are generally characterized by presence of catalytic water molecules within the active site which are required for enzyme catalytic activity (Tamilselvi, Nethaji, & Mugesh, 2006;Wommer et al, 2002). Results showed the presence of six water molecules at molecule number 531, 538, 540, 562, 573 and 591 associated with the active site of NDM-2.…”