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β-Lactamases and β-Lactamase Inhibitors in the 21st Century

The β-lactams retain a central place in the antibacterial armamentarium. In Gram-negative bacteria, β-lactamase enzymes that hydrolyze the amide bond of the four-membered β-lactam ring are the primary resistance mechanism, with multiple enzymes disseminating on mobile genetic elements across opportu...

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Autores principales: Tooke, Catherine L., Hinchliffe, Philip, Bragginton, Eilis C., Colenso, Charlotte K., Hirvonen, Viivi H.A., Takebayashi, Yuiko, Spencer, James
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723624/
https://www.ncbi.nlm.nih.gov/pubmed/30959050
http://dx.doi.org/10.1016/j.jmb.2019.04.002
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author Tooke, Catherine L.
Hinchliffe, Philip
Bragginton, Eilis C.
Colenso, Charlotte K.
Hirvonen, Viivi H.A.
Takebayashi, Yuiko
Spencer, James
author_facet Tooke, Catherine L.
Hinchliffe, Philip
Bragginton, Eilis C.
Colenso, Charlotte K.
Hirvonen, Viivi H.A.
Takebayashi, Yuiko
Spencer, James
author_sort Tooke, Catherine L.
collection PubMed
description The β-lactams retain a central place in the antibacterial armamentarium. In Gram-negative bacteria, β-lactamase enzymes that hydrolyze the amide bond of the four-membered β-lactam ring are the primary resistance mechanism, with multiple enzymes disseminating on mobile genetic elements across opportunistic pathogens such as Enterobacteriaceae (e.g., Escherichia coli) and non-fermenting organisms (e.g., Pseudomonas aeruginosa). β-Lactamases divide into four classes; the active-site serine β-lactamases (classes A, C and D) and the zinc-dependent or metallo-β-lactamases (MBLs; class B). Here we review recent advances in mechanistic understanding of each class, focusing upon how growing numbers of crystal structures, in particular for β-lactam complexes, and methods such as neutron diffraction and molecular simulations, have improved understanding of the biochemistry of β-lactam breakdown. A second focus is β-lactamase interactions with carbapenems, as carbapenem-resistant bacteria are of grave clinical concern and carbapenem-hydrolyzing enzymes such as KPC (class A) NDM (class B) and OXA-48 (class D) are proliferating worldwide. An overview is provided of the changing landscape of β-lactamase inhibitors, exemplified by the introduction to the clinic of combinations of β-lactams with diazabicyclooctanone and cyclic boronate serine β-lactamase inhibitors, and of progress and strategies toward clinically useful MBL inhibitors. Despite the long history of β-lactamase research, we contend that issues including continuing unresolved questions around mechanism; opportunities afforded by new technologies such as serial femtosecond crystallography; the need for new inhibitors, particularly for MBLs; the likely impact of new β-lactam:inhibitor combinations and the continuing clinical importance of β-lactams mean that this remains a rewarding research area.
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spelling pubmed-67236242019-09-10 β-Lactamases and β-Lactamase Inhibitors in the 21st Century Tooke, Catherine L. Hinchliffe, Philip Bragginton, Eilis C. Colenso, Charlotte K. Hirvonen, Viivi H.A. Takebayashi, Yuiko Spencer, James J Mol Biol Review The β-lactams retain a central place in the antibacterial armamentarium. In Gram-negative bacteria, β-lactamase enzymes that hydrolyze the amide bond of the four-membered β-lactam ring are the primary resistance mechanism, with multiple enzymes disseminating on mobile genetic elements across opportunistic pathogens such as Enterobacteriaceae (e.g., Escherichia coli) and non-fermenting organisms (e.g., Pseudomonas aeruginosa). β-Lactamases divide into four classes; the active-site serine β-lactamases (classes A, C and D) and the zinc-dependent or metallo-β-lactamases (MBLs; class B). Here we review recent advances in mechanistic understanding of each class, focusing upon how growing numbers of crystal structures, in particular for β-lactam complexes, and methods such as neutron diffraction and molecular simulations, have improved understanding of the biochemistry of β-lactam breakdown. A second focus is β-lactamase interactions with carbapenems, as carbapenem-resistant bacteria are of grave clinical concern and carbapenem-hydrolyzing enzymes such as KPC (class A) NDM (class B) and OXA-48 (class D) are proliferating worldwide. An overview is provided of the changing landscape of β-lactamase inhibitors, exemplified by the introduction to the clinic of combinations of β-lactams with diazabicyclooctanone and cyclic boronate serine β-lactamase inhibitors, and of progress and strategies toward clinically useful MBL inhibitors. Despite the long history of β-lactamase research, we contend that issues including continuing unresolved questions around mechanism; opportunities afforded by new technologies such as serial femtosecond crystallography; the need for new inhibitors, particularly for MBLs; the likely impact of new β-lactam:inhibitor combinations and the continuing clinical importance of β-lactams mean that this remains a rewarding research area. Elsevier 2019-08-23 /pmc/articles/PMC6723624/ /pubmed/30959050 http://dx.doi.org/10.1016/j.jmb.2019.04.002 Text en © 2019 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Tooke, Catherine L.
Hinchliffe, Philip
Bragginton, Eilis C.
Colenso, Charlotte K.
Hirvonen, Viivi H.A.
Takebayashi, Yuiko
Spencer, James
β-Lactamases and β-Lactamase Inhibitors in the 21st Century
title β-Lactamases and β-Lactamase Inhibitors in the 21st Century
title_full β-Lactamases and β-Lactamase Inhibitors in the 21st Century
title_fullStr β-Lactamases and β-Lactamase Inhibitors in the 21st Century
title_full_unstemmed β-Lactamases and β-Lactamase Inhibitors in the 21st Century
title_short β-Lactamases and β-Lactamase Inhibitors in the 21st Century
title_sort β-lactamases and β-lactamase inhibitors in the 21st century
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723624/
https://www.ncbi.nlm.nih.gov/pubmed/30959050
http://dx.doi.org/10.1016/j.jmb.2019.04.002
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