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
Multiyear, Multinational Survey of the Incidence and Global Distribution of Metallo-β-Lactamase-Producing Enterobacteriaceae and Pseudomonas aeruginosa.
Krystyna M. Kazmierczak,Sharon Rabine,Meredith Hackel,Robert E. McLaughlin,Douglas J. Biedenbach,Samuel K. Bouchillon,Daniel F. Sahm,Patricia A. Bradford +7 more
TL;DR: The in vitro activities of all tested antibiotics against MBL-positive Enterobacteriaceae were significantly reduced with the exception of aztreonam-avibactam, whereas colistin was the most effective agent against M BL-positive P. aeruginosa isolates.
Journal ArticleDOI
Sequence analysis of the L1 metallo-β-lactamase from Xanthomonas maltophilia
Timothy R. Walsh,Len Hall,Stephen J. Assinder,Wright W. Nichols,Steven J. Cartwright,Alasdair P. MacGowan,Peter M. Bennett +6 more
TL;DR: The amino acid sequence deduced from the L1 β-lactamase gene of Xanthomonas maltophilia shows a significant variation from that of the CphA and Blm metallo-β- lactamases of Aeromonas hydrophila and Bacillus cereus, respectively.
Journal ArticleDOI
The zinc-reversible antimicrobial activity of neutrophil lysates and abscess fluid supernatants.
TL;DR: The suppressive effects of either human or mouse neutrophil lysates on Candida albicans growth were found to be completely reversed by micromolar quantities of zinc but not by iron or other trace elements, suggesting that the major mechanism of C. al bicans growth inhibition by abscess fluids is through competition for zinc by a cytoplasmic protein apparently released from dying neutrophils.
Journal ArticleDOI
Zinc as a cofactor for cephalosporinase from Bacillus cereus 569.
L. D. Sabath,E. P. Abraham +1 more
Journal ArticleDOI
Plasmid-Encoded Metallo-β-Lactamase (IMP-6) Conferring Resistance to Carbapenems, Especially Meropenem
Hisakazu Yano,Akio Kuga,Ryoichi Okamoto,Hidero Kitasato,Toshimitsu Kobayashi,Matsuhisa Inoue +5 more
TL;DR: Although IMP-6 has reduced activity against penicillins due to this point mutation, pKU501 confers resistance to a variety of antimicrobial agents because it also produces TEM-1-type enzyme.