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Cited by 1,016

The DOI matches its Crossref record; 202 of the 202 references it cites were found in a registry or an index.

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

Open access
Tooke, Catherine L., Hinchliffe, Philip, Bragginton, Eilis C., Colenso, Charlotte K., Hirvonen, Viivi H.A., Takebayashi, Yuiko, Spencer, James·2019·Journal of Molecular Biology

Abstract

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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Metadata

Authors
Tooke, C. L., Hinchliffe, P., Bragginton, E. C., Colenso, C. K., Hirvonen, V. H. A., Takebayashi, Y., & Spencer, J.
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2019-08
Volume
431
Issue
18
Pages
3472-3500
ISSN
0022-2836 (ISSN-L)
OpenAlex
W2925800094
Cited by
1,016
References
202
FWCI
27.30
Type
journal article
Language
en
Open access
hybrid

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CoChat. (2026). Citation check: β-Lactamases and β-Lactamase Inhibitors in the 21st Century. https://app.cochat.ai/papers/10.1016/j.jmb.2019.04.002
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Tooke, C. L., Hinchliffe, P., Bragginton, E. C., Colenso, C. K., Hirvonen, V. H. A., Takebayashi, Y., & Spencer, J. (2019). β-Lactamases and β-Lactamase Inhibitors in the 21st Century. Journal of Molecular Biology. https://doi.org/10.1016/j.jmb.2019.04.002

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