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
The Mechanisms of Catalysis by Metallo β-Lactamases
Michael I. Page,Adriana Badarau +1 more
TL;DR: An intrinsic property of binuclear metallo hydrolytic enzymes that depend on a metal-bound water both as the attacking nucleophile and as a ligand for the second metal-ion is that this water molecule has to be replaced to maintain the catalytic cycle.
Journal ArticleDOI
Crystal Structure of Pseudomonas aeruginosa SPM-1 Provides Insights into Variable Zinc Affinity of Metallo-β-lactamases
Tanya A. Murphy,Lucy E. Catto,Stephen E. Halford,Andrea T. Hadfield,Wladek Minor,Timothy R. Walsh,James Spencer +6 more
TL;DR: The crystal structure of SPM-1 is reported and it is predicted that S PM-1 possesses the capacity to evolve variants of enhanced catalytic activity by point mutations altering geometry and hydrogen bonding in the vicinity of the second Zn2+ site.
Journal ArticleDOI
Structural and Mechanistic Insights into NDM-1 Catalyzed Hydrolysis of Cephalosporins
Han Feng,Jingjin Ding,Deyu Zhu,Xuehui Liu,Xueyong Xu,Ying Zhang,Shanshan Zang,Da-Cheng Wang,Wei Liu +8 more
TL;DR: The first crystal structures of NDM-1 in complex with cefuroxime and cephalexin, as well as NMR spectra monitoring cephalosporin hydrolysis catalyzed by N DM-1 are reported and it is revealed that D124 most likely plays a more structural than catalytic role.
Journal ArticleDOI
Mimicking natural evolution in metallo-β-lactamases through second-shell ligand mutations
TL;DR: Results show that the evolution of enzymatic catalysis can take place by remote mutations controlling reactivity, and MBLs are able to expand their substrate spectrum without sacrificing their inherent hydrolytic capabilities.
Journal ArticleDOI
Characterization of DIM-1, an Integron-Encoded Metallo-β-Lactamase from a Pseudomonas stutzeri Clinical Isolate in the Netherlands
Laurent Poirel,José-Manuel Rodríguez-Martínez,Nashwan Al Naiemi,Yvette J. Debets-Ossenkopp,Patrice Nordmann +4 more
TL;DR: A carbapenem-resistant Pseudomonas stutzeri strain isolated from a Dutch patient was analyzed in detail and produced a metallo-β-lactamase (MBL) whose gene was embedded in a class 1 integron containing two other gene cassettes, encoding resistance to aminoglycosides and disinfectants.