Metallo-β-Lactamases: A Major Threat to Human Health

Abstract

Antibiotic resistance is one of the most significant challenges facing global healthcare. Since the 1940s, antibiotics have been used to fight infections, initially with penicillin and subsequently with various derivatives including cephalosporins, carbapenams and monobactams. A common characteristic of these antibiotics is the four-membered β-lactam ring. Alarmingly, in recent years an increasing number of bacteria have become resistant to these antibiotics. A major strategy employed by these pathogens is to use Zn(II)-dependent enzymes, the metallo-β-lactamases (MBLs), which hydrolyse the β-lactam ring. Clinically useful MBL inhibitors are not yet available. Consequently, MBLs remain a major threat to human health. In this review biochemical properties of MBLs are discussed, focusing in particular on the interactions between the enzymes and the functionally essential metal ions. The precise role(s) of these metal ions is still debated and may differ between different MBLs. However, since they are required for catalysis, their binding site may present an alternative target for inhibitor design.

Enhancement of antibiotic-activity through complexation with metal ions - Combined ITC, NMR, enzymatic and biological studies

“…[9] Different types of β-lactamases have evolved to disable new generations of β-lactam antibiotics, with metallo-β-lactamases (MBLs) being one of the major causes of widespread antibacterial resistance towards the important carbapenem class of antibiotics. [11,12] These metallohydrolases require at least one metal ion in the active site to coordinate to the nucleophile required for hydrolysis. [7][8][9][10][13][14][15][16][17] In recent years, several groups have been…”

Kinetic, mechanistic, structural and spectroscopic investigations of Bimetallic Metallohydrolases

“…Important residues for substrate binding are also . While diverse BMHs may vary greatly in their polypeptide sequence and biological functions, their active site geometries tend to be rather conserved ions in the active site are bridged by the nucleophilic hydroxide (3) . In purple acid phosphatase (PAP), the only BMH where the necessity for a heterobinuclear metal centre of the form Fe 3+ -M 2+ (with M = Fe, Zn or Mn) has been established, the two metal ions are also bridged by a hydroxide in addition to an oxygen from an aspartate residue.…”

“…10 ) and as such it is diamagnetic. Zn is able to form tetrahedral, octahedral or trigonal bipyramidal complexes, with the latter being the most common geometry found in metalloenzymes (3) . The most common ligands in proteins are histidine residues (16)(17)(18)(19) .…”

“…These compounds are very effective in impeding the enzymes involved in the generation of peptidoglycans in the cell wall of pathogenic bacteria (3,7,(63)(64)(65) . In Gram negative bacteria, β-lactam antibiotics invade bacteria via passing through the cell membrane and cell walls.…”

“…Groups A, C and D are serine-β-lactamases (SBLs), which employ a serine residue to initiate the hydrolysis of the β-lactam ring (i.e. its opening), whilst group B contains the MBLs, which require either one or two metal ions in their active site as essential cofactors for catalysis (3,7,65,67,68) . (69)(70)(71)(72)(73) , carboxylate (74) or tertazole (75) compounds.…”