10.1016\/j.jmb.2019.04.002<\/a><\/p>\nAuthors:<\/h4>\n
Catherine L. Tooke, Philip Hinchliffe, \u00c9il\u00eds C. Bragginton, Charlotte K. Colenso, Viivi H. A. Hirvonen, Yuiko Takebayashi, James Spencer<\/p>\n
Abstract:<\/h4>\n
The \u03b2-lactams retain a central place in the antibacterial armamentarium. In Gram-negative bacteria, \u03b2-lactamase enzymes that hydrolyze the amide bond of the four-membered \u03b2-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). \u03b2-Lactamases divide into four classes; the active-site serine \u03b2-lactamases (classes A, C and D) and the zinc-dependent or metallo-\u03b2-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 \u03b2-lactam complexes, and methods such as neutron diffraction and molecular simulations, have improved understanding of the biochemistry of \u03b2-lactam breakdown. A second focus is \u03b2-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 \u03b2-lactamase inhibitors, exemplified by the introduction to the clinic of combinations of \u03b2-lactams with diazabicyclooctanone and cyclic boronate serine \u03b2-lactamase inhibitors, and of progress and strategies toward clinically useful MBL inhibitors. Despite the long history of \u03b2-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 \u03b2-lactam:inhibitor combinations and the continuing clinical importance of \u03b2-lactams mean that this remains a rewarding research area.<\/p>\n","protected":false},"excerpt":{"rendered":"
DOI: 10.1016\/j.jmb.2019.04.002 Authors: Catherine L. Tooke, Philip Hinchliffe, \u00c9il\u00eds C. Bragginton, Charlotte K. Colenso, Viivi H. A. Hirvonen, Yuiko Takebayashi, James Spencer Abstract: The \u03b2-lactams retain a central place in the antibacterial armamentarium. In Gram-negative bacteria, \u03b2-lactamase enzymes that hydrolyze the amide bond of the four-membered \u03b2-lactam ring are the primary resistance mechanism, with multiple […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[5],"tags":[41],"class_list":["post-742","post","type-post","status-publish","format-standard","hentry","category-freeze-quench","tag-biochemistry"],"_links":{"self":[{"href":"https:\/\/citations.tools.bio-logic.fr\/index.php?rest_route=\/wp\/v2\/posts\/742","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/citations.tools.bio-logic.fr\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/citations.tools.bio-logic.fr\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/citations.tools.bio-logic.fr\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/citations.tools.bio-logic.fr\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=742"}],"version-history":[{"count":0,"href":"https:\/\/citations.tools.bio-logic.fr\/index.php?rest_route=\/wp\/v2\/posts\/742\/revisions"}],"wp:attachment":[{"href":"https:\/\/citations.tools.bio-logic.fr\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=742"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/citations.tools.bio-logic.fr\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=742"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/citations.tools.bio-logic.fr\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=742"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}