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
Structure and Mechanism-Guided Design of Dual Serine/Metallo-Carbapenemase Inhibitors.
TL;DR: This Perspective is the first systematic investigation of all chemotypes, modes of inhibition, and crystal structures of dual serine/metallo-carbapenemase inhibitors, and their mechanism of action to overcome the carbapenems resistance issue.
Journal ArticleDOI
Metallo-β-lactamase-mediated antimicrobial resistance and progress in inhibitor discovery.
TL;DR: This article reviewed the classification, structures, substrate profiles, and inhibition mechanisms of metallo-β-lactamases, highlighting current clinical problems due to MBL-mediated resistance and progress in understanding and combating MBL mediated resistance.
Journal ArticleDOI
A hydroxide lock for metallo-β-lactamases
Hongyan Li,Hongzhe Sun +1 more
TL;DR: Indole-2-carboxylates have been developed as broad-spectrum inhibitors for MBLs that take advantage of key elements of both MBL substrates and products and work by locking a hydroxide.
Journal ArticleDOI
Bismuth complex of quinoline thiosemicarbazone restores carbapenem sensitivity in NDM-1-positive Klebsiella pneumoniae.
Mirco Scaccaglia,Martina Rega,C. Bacci,Dario Giovanardi,Silvana Pinelli,Giorgio Pelosi,Franco Bisceglie +6 more
TL;DR: In this article , the synergistic relationship between the compounds and meropenem have been tested in a combination therapy in carbapenem-resistant Klebsiella pneumoniae (NTCT14331) carrying the NDM-1 gene.
Journal ArticleDOI
Optimization of 1,2,4-Triazole-3-thiones toward Broad-Spectrum Metallo-β-lactamase Inhibitors Showing Potent Synergistic Activity on VIM- and NDM-1-Producing Clinical Isolates.
Alice Legru,Federica Verdirosa,Yen Vo-Hoang,G. Tassone,Filippo Vascon,Caitlyn A. Thomas,Filomena Sannio,Giuseppina Corsica,Manuela Benvenuti,Georges Feller,Rémi Coulon,Francesca Marcoccia,Savannah R. Devente,Ezeddine Bouajila,Catherine Piveteau,Florence Leroux,Rebecca Deprez-Poulain,Benoit Deprez,Patricia Licznar-Fajardo,Michael W. Crowder,Laura Cendron,Cecilia Pozzi,Stefano Mangani,Jean Denis Docquier,Jean-François Hernandez,Laurent Gavara +25 more
TL;DR: In this paper , a series of 1,2,4-triazole-3-thione-based inhibitors displaying an α-amino acid substituent, which amine was mono- or disubstituted by (hetero)aryl groups.
References
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Journal ArticleDOI
Loop-mediated isothermal amplification of DNA
Tsugunori Notomi,Hiroto Okayama,Harumi Otawara-shi Masubuchi,Toshihiro Yonekawa,Keiko Watanabe,Nobuyuki Amino,Tetsu Hase +6 more
TL;DR: A novel method that amplifies DNA with high specificity, efficiency and rapidity under isothermal conditions that employs a DNA polymerase and a set of four specially designed primers that recognize a total of six distinct sequences on the target DNA.
Journal ArticleDOI
Molecular Basis of Bacterial Outer Membrane Permeability Revisited
TL;DR: This review summarizes the development in the field since the previous review and begins to understand how this bilayer of the outer membrane can retard the entry of lipophilic compounds, owing to increasing knowledge about the chemistry of lipopolysaccharide from diverse organisms and the way in which lipopoly Saccharide structure is modified by environmental conditions.
Journal ArticleDOI
SignalP 5.0 improves signal peptide predictions using deep neural networks
Jose Juan Almagro Armenteros,Konstantinos D. Tsirigos,Casper Kaae Sønderby,Thomas Nordahl Petersen,Ole Winther,Ole Winther,Søren Brunak,Søren Brunak,Gunnar von Heijne,Gunnar von Heijne,Henrik Nielsen +10 more
TL;DR: A deep neural network-based approach that improves SP prediction across all domains of life and distinguishes between three types of prokaryotic SPs is presented.
Journal ArticleDOI
A functional classification scheme for beta-lactamases and its correlation with molecular structure.
TL;DR: These enzymes are the major cause of bacterial resistance to b-lactam antibiotics and have been the subject of extensive microbiological, biochemical, and genetic investigations.
Journal ArticleDOI
Characterization of a New Metallo-β-Lactamase Gene, blaNDM-1, and a Novel Erythromycin Esterase Gene Carried on a Unique Genetic Structure in Klebsiella pneumoniae Sequence Type 14 from India
Dongeun Yong,Mark Toleman,Christian G. Giske,Hyun Sun Cho,Kristina Sundman,Kyungwon Lee,Timothy R. Walsh +6 more
TL;DR: A Swedish patient of Indian origin traveled to New Delhi, India, and acquired a urinary tract infection caused by a carbapenem-resistant Klebsiella pneumoniae strain that typed to the sequence type 14 complex, showing broad resistance carried on these plasmids.