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
Thiols as Classical and Slow-Binding Inhibitors of IMP-1 and Other Binuclear Metallo-β-lactamases†
TL;DR: Studies on the thiol-mediated inhibition of the binuclear forms of Bacteroides fragilis and Bacillus cereus have revealed that while CcrA was instantaneously albeit moderately inhibited by mercaptans, BcII mimicked IMP-1 in its interaction with thiols, proposed to be due partly to the structural divergence of these proteins in the vicinity of Zn2.
Journal ArticleDOI
Spectroscopic and Mechanistic Studies of Heterodimetallic Forms of Metallo-β-lactamase NDM‑1
Hao Yang,Mahesh Aitha,Amy R. Marts,Alyssa Hetrick,Brian Bennett,Michael W. Crowder,David L. Tierney +6 more
TL;DR: This marks the first preparation of a metallo-β-lactamase selectively substituted with a paramagnetic metal ion, Co(II), either in the Zn1 (CoCd-NDM-1) or in theZn2 site (ZnCo-NDm-1), as well as both (CoCo- NDM- 1).
Journal ArticleDOI
Structural determinants of substrate binding to Bacillus cereus metallo-β-lactamase
TL;DR: The apoenzyme could not bind any of the substrates, but binding was restored when the apoen enzyme was reconstituted with Zn(II), revealing that the metal ions are the main determinants of substrate binding.
Journal ArticleDOI
Biochemical and Structural Characterization of the Subclass B1 Metallo-β-Lactamase VIM-4
Patricia Lassaux,Daouda A K Traore,Elodie Loisel,Adrien Favier,Jean Denis Docquier,Jean Sohier,Clémentine Laurent,Carine Bebrone,Jean-Marie Frère,Jean-Luc Ferrer,Moreno Galleni +10 more
TL;DR: Study of the thermal stability and the activity of the holo- and apo-VIM-4 enzymes revealed that Zn2+ ions have a pronounced stabilizing effect on the enzyme and are necessary for preserving the structure.
Journal ArticleDOI
N-Heterocyclic dicarboxylic acids: Broad-spectrum inhibitors of metallo-β-lactamases with co-antibacterial effect against antibiotic-resistant bacteria
Lei Feng,Ke-Wu Yang,Li-Sheng Zhou,Jian-Min Xiao,Xia Yang,Le Zhai,Yi-Lin Zhang,Michael W. Crowder +7 more
TL;DR: It is demonstrated that N-heterocyclic dicarboxylic acids 1a-c and pyridylmercaptothiadiazoles 2a,b are good scaffolds for future broad-spectrum inhibitors of the MβLs.