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
Is it necessary to change the classification of β-lactamases?
Journal ArticleDOI
Moraxella (Branhamella) catarrhalis BRO beta-lactamase: a lipoprotein of gram-positive origin?
Hester J. Bootsma,Piet C. Aerts,George Posthuma,Theo Harmsen,Jan Verhoef,Hans van Dijk,Frits R. Mooi +6 more
TL;DR: This work shows that BRO is expressed as a 33-kDa lipoprotein associated with the inner leaflet of the outer membrane in Moraxella catarrhalis strains, the first description of a lipidated beta-lactamase in a gram-negative species.
Journal ArticleDOI
A Novel New Delhi Metallo-β-Lactamase Variant, NDM-14, Isolated in a Chinese Hospital Possesses Increased Enzymatic Activity against Carbapenems
Dayang Zou,Yong Huang,Xiangna Zhao,Wei Liu,Derong Dong,Huan Li,Xuesong Wang,Simo Huang,Xiao Wei,Xiabei Yan,Zhan Yang,Yigang Tong,Liuyu Huang,Jing Yuan +13 more
TL;DR: A novel New Delhi metallo-β-lactamase (NDM) variant, NDM-14, was identified in clinical isolate Acinetobacter lwoffii JN49-1, which was recovered from an intensive care unit patient at a local hospital in China.
Journal ArticleDOI
Effect of Ph on the Active Site of an Arg121Cys Mutant of the Metallo-Beta-Lactamase from Bacillus Cereus: Implications for the Enzyme Mechanism
TL;DR: Crystal structures of the Arg121Cys mutant of the B. cereus 569/H/9 enzyme provide experimental evidence for an earlier proposed mechanism in which protonation of Asp120 and the Zn1-bound hydroxide are the two events that lead to the loss of activity at low pH.
Journal ArticleDOI
Kinetics and Phospholipid Specificity of Apolipoprotein N-Acyltransferase
TL;DR: Kinetics of Lnt using phosphatidylethanolamine as an acyl donor and FSL-1 as a substrate were consistent with a ping-pong type mechanism, demonstrating slow acyl-enzyme intermediate formation and rapid N-acyl transfer to the apolipopeptide in vitro.