Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design

Abstract

Antimicrobial resistance is one of the major problems in current practical medicine. The spread of genes coding for resistance determinants among bacteria challenges the use of approved antibiotics, narrowing the options for treatment. Resistance to carbapenems, last resort antibiotics, is a major concern. Metallo-β-lactamases (MBLs) hydrolyze carbapenems, penicillins, and cephalosporins, becoming central to this problem. These enzymes diverge with respect to serine-β-lactamases by exhibiting a different fold, active site, and catalytic features. Elucidating their catalytic mechanism has been a big challenge in the field that has limited the development of useful inhibitors. This review covers exhaustively the details of the active-site chemistries, the diversity of MBL alleles, the catalytic mechanism against different substrates, and how this information has helped developing inhibitors. We also discuss here different aspects critical to understand the success of MBLs in conferring resistance: the molecular determinants of their dissemination, their cell physiology, from the biogenesis to the processing involved in the transit to the periplasm, and the uptake of the Zn(II) ions upon metal starvation conditions, such as those encountered during an infection. In this regard, the chemical, biochemical and microbiological aspects provide an integrative view of the current knowledge of MBLs.

Dual Activity BLEG-1 from Bacillus lehensis G1 Revealed Structural Resemblance to B3 Metallo-β-Lactamase and Glyoxalase II: An Insight into Its Enzyme Promiscuity and Evolutionary Divergence

“…Metallo-hydrolase-like MBL-fold superfamily of proteins is a large and ancient group of proteins that are widely distributed over the kingdoms of bacteria, archaea, and eukarya. Sequence, structure, and biochemical studies revealed that the superfamily consists of members with diverse functions, consisting of class B β-lactamase, glyoxalase II (GLXII), N-acyl-L-homoserine lactonase (AHL), persulfide dioxygenase, flavodiiron protein, choline-binding protein, cleavage and polyadenylation specificity factors, arylsulfatase, 5 -exonuclease, ribonuclease, cyclic nucleotide phosphodiesterase, insecticide hydrolase, and proteins required for natural transformation competence [1][2][3][4]. Members of this superfamily contain conserved αβ/βα metallo-β-lactamase-fold (MBL-fold) domain, with two central β-sheets surrounded by solvent-exposed α-helices, and either have a mononuclear or binuclear metal binding site located at the interface of the β/β sandwich, characterized by the His-Xaa-His-Xaa-Asp-His motif [5].…”

Antimicrobial Activity of Aztreonam in Combination with Old and New β-Lactamase Inhibitors against MBL and ESBL Co-Producing Gram-Negative Clinical Isolates: Possible Options for the Treatment of Complicated Infections

“…Infections sustained by metallo-β-lactamases (MBLs)-producing bacteria pose a global challenge due to the paucity of effective antibiotic options. Despite that MBLs account only for 10% of the total β-lactamases [ 1 ], these enzymes are capable of hydrolyzing all current available β-lactams, with the exception of monobactams, such as aztreonam (ATM) [ 2 ]. Differently from serine-β-lactamases, MBLs are Zn-dependent metalloproteinases which are non-susceptible to inactivation by currently available β-lactams inhibitors (BLIs), including vaborbactam (VAB), a cyclic boronate, and avibactam (AVI), a diazabicyclooctanone (DBO) derivative [ 3 ].…”

Strategies for Zinc Uptake in Pseudomonas aeruginosa at the Host–Pathogen Interface

“…Some studies have found that non-specific porins on the cell membrane may also be involved in the transport of Zn 2+ from the outer membrane to the periplasmic space. P. aeruginosa regulates the expression of specific porins in response to Zn 2+ availability, such as OprD (Bahr et al, 2021). In addition, OprF is the most abundant non-lipoprotein outer membrane porin in P. aeruginosa, allowing ions and low molecular weight sugar molecules to pass through (Chevalier et al, 2017).…”