{"id":3960,"date":"2021-12-22T14:41:47","date_gmt":"2021-12-22T12:41:47","guid":{"rendered":"https:\/\/ospt.osi.lv\/?p=3960"},"modified":"2022-11-15T18:40:42","modified_gmt":"2022-11-15T16:40:42","slug":"imitation-of-%ce%b2-lactam-binding-enables-broad-spectrum-metallo-%ce%b2-lactamase-inhibitors","status":"publish","type":"post","link":"https:\/\/ospt.osi.lv\/imitation-of-%ce%b2-lactam-binding-enables-broad-spectrum-metallo-%ce%b2-lactamase-inhibitors\/","title":{"rendered":"38. Imitation of \u03b2-lactam binding enables broad-spectrum metallo-\u03b2-lactamase inhibitors"},"content":{"rendered":"<div class=\"wpb-content-wrapper\"><p>[vc_row][vc_column][vc_column_text]Brem, J.; Panduwawala, T.; Hansen, J. U.; Hewitt, J.; Liepins, E.; Donets, P.; Espina, L.; Farley, A. J. M.; Shubin, K; Campillos, G. G.; Kiuru, P.; Shishodia, S.; Krahn, D.; Le\u015bniak, R. K.; Schmidt (Adrian), J.; Calvopi\u00f1a, K.; Turrientes, M. C.; Kavanagh, M. E.; Lubriks, D.; Hinchliffe, P.; Langley, G. W.; Aboklaish, A. F.; Eneroth, A.; Backlund, M.; Baran, A. G.; Nielsen, E. I.; Speake, M.; Kuka, J.; Robinson, J.; Grinberga, S.; Robinson, L.; McDonough, M. A.; Rydzik, A. M.; Leissing, T. M.; Jimenez-Castellanos, J. C.; Avison, M. B; Pinto, S. S.; Pannifer, A. D.; Martjuga, M.; Widlake, E.; Priede, M.; Navratilova, I. H.; Gniadkowski, M.; Belfrage, A. K.; Brandt, P.; Yli-Kauhaluoma, j.; Bacque, E.; Page, M. G. P.; Bj\u00f6rkling, F.; Tyrrell, J. M.; Spencer, J.; Lang, P. A.; Baranczewski, P.; Cant\u00f3n, R.; McElroy, S. P.; Jones, P. S.; Baquero, F.; Suna, E.; Morrison, A.; Walsh, T. R.; Schofield, C. J.<em> Nat. Chem<\/em> <strong>2022<\/strong>, <em>14<\/em>, 15-24.<\/p>\n<p>DOI: <a title=\"Imitation of \u03b2-lactam binding enables broad-spectrum metallo-\u03b2-lactamase inhibitors\" href=\"https:\/\/doi.org\/10.1038\/s41557-021-00831-x\" target=\"_blank\" rel=\"nofollow noopener\">10.1038\/s41557-021-00831-x<\/a><\/p>\n<p><!--more--><\/p>\n<h4>Abstract<\/h4>\n<p style=\"text-align: justify;\">Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-\u03b2-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential \u03b2-lactamase stable \u03b2-lactam mimics. Subsequent structure\u2013activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL\u2013carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.<\/p>\n<p>[\/vc_column_text][\/vc_column][\/vc_row]<\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>[vc_row][vc_column][vc_column_text]Brem, J.; Panduwawala, T.; Hansen, J. U.; Hewitt, J.; Liepins, E.; Donets, P.; Espina, L.; Farley, A. J. M.; Shubin, K; Campillos, G. G.; Kiuru, P.; Shishodia, S.; Krahn, D.; Le\u015bniak, R. K.; Schmidt (Adrian), J.; Calvopi\u00f1a, K.; Turrientes, M. C.; Kavanagh, M. E.; Lubriks, D.; Hinchliffe, P.; Langley, G. W.; Aboklaish, A. F.; Eneroth, [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":3963,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"image","meta":{"_exactmetrics_skip_tracking":false,"_exactmetrics_sitenote_active":false,"_exactmetrics_sitenote_note":"","_exactmetrics_sitenote_category":0,"footnotes":""},"categories":[40,16],"tags":[],"aioseo_notices":[],"_links":{"self":[{"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/posts\/3960"}],"collection":[{"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/comments?post=3960"}],"version-history":[{"count":4,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/posts\/3960\/revisions"}],"predecessor-version":[{"id":4084,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/posts\/3960\/revisions\/4084"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/media\/3963"}],"wp:attachment":[{"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/media?parent=3960"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/categories?post=3960"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/ospt.osi.lv\/wp-json\/wp\/v2\/tags?post=3960"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}