Journal ArticleDOI
Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design.
TLDR
In this article, a review of the active site and catalytic mechanism of Metallo-β-lactamases (MBLs) is presented, and the success of MBLs in conferring resistance to carbapenems, penicillins, and cephalosporins.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.read more
Citations
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Journal ArticleDOI
β-Lactam antibiotic targets and resistance mechanisms: from covalent inhibitors to substrates.
TL;DR: This tutorial-style review of the β-lactam antibiotics provides an overview of their covalent interactions with their target proteins and resistance mechanisms, and introduces the l,d-transpeptidases, a group of bacterial enzymes involved in peptidoglycan synthesis which are also targeted by β- lactams.
Journal ArticleDOI
Metallo-β-lactamases and a tug-of-war for the available zinc at the host–pathogen interface
TL;DR: Metallo-β-lactamases (MBLs) are zinc-dependent hydrolases that inactivate virtually all β lactam antibiotics as discussed by the authors , and metal starvation is a driving force acting on MBL evolution.
Journal ArticleDOI
1,2,4-Triazole-3-thione compounds with a 4-ethyl alkyl/aryl sulfide substituent are broad-spectrum metallo-β-lactamase inhibitors with re-sensitization activity.
Alice Legru,Federica Verdirosa,Jean-François Hernandez,G. Tassone,Filomena Sannio,Manuela Benvenuti,Pierre-Alexis Conde,Guillaume Bossis,Caitlyn A. Thomas,Michael W. Crowder,Melissa Dillenberger,Katja Becker,Cecilia Pozzi,Stefano Mangani,Jean Denis Docquier,Jean Denis Docquier,Laurent Gavara +16 more
TL;DR: In this paper, the potential of compounds based on the 1,2,4-triazole-3-thione scaffold as an original ligand of the di-zinc active sites of MBLs was explored.
Journal ArticleDOI
Deciphering the evolution of metallo-β-lactamases: a journey from the test tube to the bacterial periplasm.
TL;DR: In this paper , the evolutionary traits acquired by different clinical variants of MBLs in conditions mimicking their native environment (the bacterial periplasm) and considering whether they are soluble or membrane-bound proteins are discussed.
Journal ArticleDOI
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
Gianluca Morroni,Raffaela Bressan,Simona Fioriti,Gloria D’Achille,Marina Mingoia,Oscar Cirioni,Stefano Di Bella,Aurora Piazza,Francesco Comandatore,Carola Mauri,Roberta Migliavacca,Francesco Luzzaro,Luigi Principe,Cristina Lagatolla +13 more
TL;DR: In this paper, the authors assessed the activity of the combination of Aztreonam (ATM) with old and new β-lactamases inhibitors (BLIs) against MBL and ESBL co-producing Gram-negative clinical isolates.
References
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Journal ArticleDOI
Cephalosporinases associated with outer membrane vesicles released by Bacteroides spp. protect gut pathogens and commensals against β-lactam antibiotics
Régis Stentz,Nikki Horn,Kathryn Cross,Louise J. Salt,Charles A. Brearley,David M. Livermore,Simon R. Carding +6 more
TL;DR: The production of membrane vesicles carrying surface-associated β-lactamases by Bacteroides species, which constitute a major part of the human colonic microbiota, may protect commensal bacteria and enteric pathogens, such as Salmonella Typhimurium, against β- lactam antibiotics.
Journal ArticleDOI
Antibiotic deactivation by a dizinc beta-lactamase: mechanistic insights from QM/MM and DFT studies.
Dingguo Xu,Hua Guo,Qiang Cui +2 more
TL;DR: Investigation of the initial ring-opening step in the hydrolysis of moxalactam catalyzed by the dizinc L1 beta-lactamase from Stenotrophomonas maltophilia indicates that the addition of the hydroxide nucleophile to the carbonyl carbon in the substrate lactam ring leads to a metastable intermediate via a dominant nucleophilic addition barrier.
Journal ArticleDOI
A Bird’s-Eye View of Enzyme Evolution: Chemical, Physicochemical, and Physiological Considerations
TL;DR: A bird's-eye view of the enzyme space from two angles: evolution and chemistry is described, examining various chemical reaction parameters that may have shaped the catalytic performances and active-site architectures of enzymes.
Journal ArticleDOI
Flexible Metal Binding of the Metallo-β-lactamase Domain: Glyoxalase II Incorporates Iron, Manganese, and Zinc in Vivo†
Oliver Schilling,Nathan F. Wenzel,Melissa Naylor,Andreas Vogel,Michael W. Crowder,Christopher A. Makaroff,Wolfram Meyer-Klaucke +6 more
TL;DR: The metal-ligand distances measured by X-ray absorption spectroscopy vary depending on the metal type and comply with their element-specific, characteristic values, reflecting a high degree of structural flexibility within the glyoxalase II dinuclear active site, which is considered as the structural basis for its broad metal selectivity.
Journal ArticleDOI
Novel Mechanism of Hydrolysis of Therapeutic β-Lactams byStenotrophomonas maltophilia L1 Metallo-β-lactamase
TL;DR: It is suggested that the mechanism of hydrolysis of nitrocefin by binuclear metallo-β-lactamases may be atypical and that cleavage of the β-Lactam amide bond is the rate-determining step for breakdown of the majority of β- lactam substrates by the L1 enzyme.