{"id":2822,"date":"2023-05-19T17:38:50","date_gmt":"2023-05-19T08:38:50","guid":{"rendered":"https:\/\/bionauts.jp\/?p=2822"},"modified":"2023-05-19T17:38:50","modified_gmt":"2023-05-19T08:38:50","slug":"metallo-%ce%b2-lactamase-inhibitors","status":"publish","type":"post","link":"https:\/\/bionauts.jp\/?p=2822","title":{"rendered":"Metallo-\u03b2-Lactamase Inhibitors"},"content":{"rendered":"<h3>Advantages<\/h3>\n<ul>\n<li>Higher inhibition than known metal chelator alone inhibitors of metallo-beta-lactamases<\/li>\n<li>Inhibitory effect on a wide range of metallo-beta-lactamases including NDM-1 and IMP-1<\/li>\n<li>Low cytotoxicity and acute toxicity in mice<\/li>\n<li>Novel compounds<\/li>\n<\/ul>\n<h3>Background and Technology<\/h3>\n<p>In recent years, reports of infectious disease-causing organisms that have acquired resistance to \u03b2-lactam antibiotics have been increasing, and the difficulty of treating these organisms has become an issue. The mechanism of resistance in many cases is the production of \u03b2-lactamases that degrade and inactivate \u03b2-lactam antibiotics. Metallo-\u03b2-lactamases are metalloenzymes that contain zinc in their active center, while serine \u03b2-lactamases are enzymes with a serine residue in their active center.<br \/>\nMetallo-\u03b2-lactamases exhibit broad substrate specificity, and the bacteria that produce them are a threat because they are resistant to many \u03b2-lactam antibiotics. For example, they also degrade carbapenem antibiotics, which are stable against serine beta-lactamases. In addition, metallo-\u03b2-lactamases have been identified in many species of bacteria, and multidrug resistance due to metallo-\u03b2-lactamase production by Pseudomonas aeruginosa is particularly problematic. Currently, \u03b2-lactamase inhibitors used in clinical practice include clavulanic acid, sulbactam, and tazobactam, which are effective in inhibiting serine-\u03b2-lactamase, and no inhibitor effective against metallo-\u03b2-lactamase has been put to practical use.<br \/>\nWe have demonstrated that a new group of compounds, in which a metal chelate structure is introduced into a \u03b2-lactam antibacterial agent, shows high inhibition against a wide range of metallo-\u03b2-lactamases (NMD-1, IMP-1, etc.) and has a high safety profile.<\/p>\n<table style=\"border-collapse: collapse; width: 100%;\">\n<tbody>\n<tr>\n<td style=\"width: 100%;\"><a href=\"http:\/\/bionauts.jp\/wp-content\/uploads\/2023\/05\/BK-04644.png\"><img decoding=\"async\" loading=\"lazy\" class=\"alignleft  wp-image-2823\" src=\"http:\/\/bionauts.jp\/wp-content\/uploads\/2023\/05\/BK-04644.png\" alt=\"\" width=\"713\" height=\"144\" srcset=\"https:\/\/bionauts.jp\/wp-content\/uploads\/2023\/05\/BK-04644.png 2028w, https:\/\/bionauts.jp\/wp-content\/uploads\/2023\/05\/BK-04644-300x61.png 300w, https:\/\/bionauts.jp\/wp-content\/uploads\/2023\/05\/BK-04644-1024x207.png 1024w, https:\/\/bionauts.jp\/wp-content\/uploads\/2023\/05\/BK-04644-768x155.png 768w, https:\/\/bionauts.jp\/wp-content\/uploads\/2023\/05\/BK-04644-1536x311.png 1536w, https:\/\/bionauts.jp\/wp-content\/uploads\/2023\/05\/BK-04644-1200x243.png 1200w\" sizes=\"(max-width: 709px) 85vw, (max-width: 909px) 67vw, (max-width: 984px) 61vw, (max-width: 1362px) 45vw, 600px\" \/><\/a><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<h3>Reference<\/h3>\n<ul>\n<li>Published patent application: WO2022\/239872<\/li>\n<\/ul>\n<h3>Principal Investigator<\/h3>\n<p>Tomohiro SAWA Professor (Kumamoto University Faculty of Life Science)<\/p>\n<h3>Current Stage and Next Step<\/h3>\n<ul>\n<li>The compound has been demonstrated to increase the susceptibility of E. coli (clinical isolate) expressing metallo-beta-lactamase IMP-1 to meropenem (carbapenem antibiotic) by more than 100-fold (upper left figure) and multidrug-resistant Pseudomonas aeruginosa (clinical isolate) by more than 85-fold (&lt;2\u00b5g\/ml) (upper right figure).<\/li>\n<li>No adverse events have been confirmed in cytotoxicity studies on cultured human cells and acute toxicity studies on mice.<\/li>\n<li>We plan to investigate the therapeutic efficacy and irreversibility of the inhibitory effect using mouse infection models. We are looking for partners to collaborate with for clinical development.<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<p>Project No. BK-04644<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Metallo-\u03b2-lactamase inhibitors with \u03b2-lactam and metal chelate structures<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_mi_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0},"categories":[1],"tags":[],"categories_of_inventions":[46],"disease_categories___indication":[],"asset_type":[],"development_phase":[],"medicine":[100,96],"other_than_medicine":[],"material":[],"engineering":[],"software_it":[],"aioseo_notices":[],"_links":{"self":[{"href":"https:\/\/bionauts.jp\/index.php?rest_route=\/wp\/v2\/posts\/2822"}],"collection":[{"href":"https:\/\/bionauts.jp\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/bionauts.jp\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=2822"}],"version-history":[{"count":2,"href":"https:\/\/bionauts.jp\/index.php?rest_route=\/wp\/v2\/posts\/2822\/revisions"}],"predecessor-version":[{"id":2825,"href":"https:\/\/bionauts.jp\/index.php?rest_route=\/wp\/v2\/posts\/2822\/revisions\/2825"}],"wp:attachment":[{"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=2822"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=2822"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=2822"},{"taxonomy":"categories_of_inventions","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories_of_inventions&post=2822"},{"taxonomy":"disease_categories___indication","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fdisease_categories___indication&post=2822"},{"taxonomy":"asset_type","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fasset_type&post=2822"},{"taxonomy":"development_phase","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fdevelopment_phase&post=2822"},{"taxonomy":"medicine","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fmedicine&post=2822"},{"taxonomy":"other_than_medicine","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fother_than_medicine&post=2822"},{"taxonomy":"material","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fmaterial&post=2822"},{"taxonomy":"engineering","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fengineering&post=2822"},{"taxonomy":"software_it","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fsoftware_it&post=2822"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}