{"id":15195,"date":"2019-02-18T17:00:40","date_gmt":"2019-02-18T16:00:40","guid":{"rendered":"https:\/\/news.embl.de\/?p=15195"},"modified":"2024-03-22T11:17:16","modified_gmt":"2024-03-22T10:17:16","slug":"tuberculosis-suicide","status":"publish","type":"post","link":"https:\/\/www.embl.org\/news\/science\/tuberculosis-suicide\/","title":{"rendered":"Cell death trigger in tuberculosis bacteria"},"content":{"rendered":"\n<p>Tuberculosis (TB) is one of the top ten causes of death worldwide. In 2017, 10 million people around the world fell ill with TB and 1.3 million died. The genome of the bacterium that causes TB holds a special toxin-antitoxin system with spectacular action: once the toxin is activated, all bacterial cells die, stopping the disease. An international research team co-led by the Wilmanns group at EMBL in Hamburg investigated this promising feature for therapeutic targets. They now share the first high-resolution details of the system in <em>Molecular Cell<\/em>.<\/p>\n\n\n\n<p><em>Mycobacterium tuberculosis<\/em> is the bacterium that causes TB in humans. Its genome holds 80 so-called toxin-antitoxin (TA) systems: sets of closely linked genes that encode both a toxic protein and an antitoxin: a toxin-neutralising antidote.<\/p>\n\n\n\n<p>When the bacteria are growing normally, toxin activity is blocked by the antitoxin\u2019s presence. But under stress conditions such as lack of nutrients, dedicated enzymes rapidly degrade the antitoxin molecules. This activates the toxin proteins in the cell and slows down the growth of the bacteria, allowing them to survive the stressful environment.<\/p>\n\n\n\n<p>One particular TA system has a more drastic effect: in the absence of the antitoxin, the toxin kills the bacteria. As this system holds potential for therapeutic targets, researchers from EMBL Hamburg, the IPBS at the CNRS\/Universit\u00e9 de Toulouse, and the Crick Institute in London joined forces to study this TA system in more detail.<\/p>\n\n\n\n<p>\u201cOur goal was to see the TA system\u2019s structure, so we could try to understand and even manipulate it. It was as if we were working blindly before\u201d, says Annabel Parret, EMBL staff scientist in the Wilmanns group, who led the project.<\/p>\n\n\n\n<figure class=\"vf-figure wp-block-image alignnone wp-image-15339 size-full\"><img loading=\"lazy\" decoding=\"async\" width=\"639\" height=\"425\" class=\"vf-figure__image\" src=\"https:\/\/news.embl.de\/wp-content\/uploads\/2019\/02\/Structure-ib.jpg\" alt=\"\" class=\"wp-image-15339\" srcset=\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2019\/02\/Structure-ib.jpg 639w, https:\/\/www.embl.org\/news\/wp-content\/uploads\/2019\/02\/Structure-ib-300x200.jpg 300w, https:\/\/www.embl.org\/news\/wp-content\/uploads\/2019\/02\/Structure-ib-293x195.jpg 293w\" sizes=\"auto, (max-width: 639px) 100vw, 639px\" \/><figcaption class=\"vf-figure__caption\">The high-resolution structure of the toxin-antitoxin system. CREDIT: EMBL<\/figcaption><\/figure>\n\n\n\n<p>The high-resolution structure \u2013 solved within eight months by first author Diana Freire \u2013 revealed a large and compact system with a double-doughnut shape. \u201cIt looks like a diamond, and it is very stable,\u201d says EMBL group leader Matthias Wilmanns. The structure resembles the toxins of cholera and diphtheria: diseases that caused epidemics with hundreds of thousands of people dying even within the past 100 years.<\/p>\n\n\n\n<p>Knowledge of the structure gave important guidance for further studying the system\u2019s biochemistry \u2013 a challenging part of the project. By using an interdisciplinary approach, the team were able to discover the details of the TA system\u2019s mode of action. When the toxin dissociates from its antidote, it becomes activated and starts to degrade essential cellular metabolites called NAD+ molecules. This \u201csuicide\u201d activity ultimately leads to the death of all bacterial cells. Why the bacteria have such a suicide system is puzzling, but there is no doubt it has the potential to be exploited as a drug target.<\/p>\n\n\n\n<blockquote class=\"vf-blockquote\"><p>If we find molecules that can disrupt the TA system \u2013 and thus trigger cell death \u2013 in TB patients, that would be the perfect drug.<\/p><\/blockquote>\n\n\n\n<p>&#8220;Our collaborators in Toulouse were already able to extend the lifetime of mice infected with TB by activating the toxin in a controlled way&#8221;,&nbsp;says Parret. \u201cIf we find molecules that can disrupt the TA system \u2013 and thus trigger cell death \u2013 in TB patients, that would be the perfect drug.\u201d<\/p>\n\n\n\n<p>The team will now screen thousands of small molecules to see if they have this capability. However, the structure of the TA system is so stable that it will be a big challenge to find an entry point where they can go in to break it. Wilmanns: \u201cBut if we succeed, this could be a new approach for treating TB and other infectious diseases.\u201d<\/p>\n\n\n\n<p><em>This project was a collaboration between researchers from the Wilmanns group at EMBL Hamburg and the Neyrolles group at the IPBS, CNRS\/Universit\u00e9 de Toulouse, and involved the Carvalho group at the Francis Crick Institute in London. The research team has started a partnership to work towards a potential TB drug, through EMBL\u2019s technology transfer arm EMBLEM.<\/em><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Suicide system in tuberculosis bacteria might hold key to treatment<\/p>\n","protected":false},"author":58,"featured_media":15337,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[2,17591],"tags":[580,53,1748,765,764,306],"embl_taxonomy":[9596,19039,19403],"class_list":["post-15195","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-science","category-science-technology","tag-bacteria","tag-hamburg","tag-press-release","tag-toxin","tag-tuberculosis","tag-wilmanns","embl_taxonomy-embl-hamburg","embl_taxonomy-matthias-wilmanns","embl_taxonomy-wilmanns-group"],"acf":{"article_intro":"<p>Suicide system in tuberculosis bacteria might hold key to treatment<\/p>\n","related_links":[{"link_description":"Research of the Wilmanns group","link_url":"http:\/\/www.embl-hamburg.de\/research\/unit\/wilmanns\/"}],"article_sources":[{"source_description":"<p>Freire, D.M., Gutierrez, C., et al. An NAD+ phosphorylase toxin triggers Mycobacterium tuberculosis cell death. Molecular Cell, published online 18 February 2019. DOI: 10.1016\/j.molcel.2019.01.028<\/p>\n","source_link_url":"https:\/\/www.cell.com\/molecular-cell\/fulltext\/S1097-2765(19)30048-6"}],"vf_locked":false,"featured":false,"color":"#007B53","link_color":"#fff","show_featured_image":false,"in_this_article":false,"youtube_url":"","mp4_url":"","video_caption":"","translations":false,"press_contact":"EMBL Generic"},"embl_taxonomy_terms":[{"uuid":"a:3:{i:0;s:36:\"b14d3f13-5670-44fb-8970-e54dfd9c921a\";i:1;s:36:\"89e00fee-87f4-482e-a801-4c3548bb6a58\";i:2;s:36:\"613c4de5-1775-447f-af71-4b07085318e9\";}","parents":[],"name":["EMBL Hamburg"],"slug":"embl-hamburg","description":"Where &gt; All EMBL sites &gt; EMBL Hamburg"},{"uuid":"a:2:{i:0;s:36:\"4428d1fd-441a-4d6d-a1c5-5dcf5665f213\";i:1;s:36:\"c1800a73-a9f4-4389-887c-f069f4ebf475\";}","parents":[],"name":["Matthias Wilmanns"],"slug":"matthias-wilmanns","description":"Who &gt; Matthias Wilmanns"},{"uuid":"a:3:{i:0;s:36:\"302cfdf7-365b-462a-be65-82c7b783ebf7\";i:1;s:36:\"2dc39890-6c01-47bf-ac78-d42abdb10079\";i:2;s:36:\"b7081976-e7c1-4678-ab00-3e02d20e9e87\";}","parents":[],"name":["Wilmanns Group"],"slug":"wilmanns-group","description":"What &gt; Structural Biology (EMBL Hamburg) &gt; Wilmanns Group"}],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v26.2 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>Cell death trigger in tuberculosis bacteria | EMBL<\/title>\n<meta name=\"description\" content=\"The suicide system in tuberculosis (TB) bacteria might hold the key to the treatment of TB, one of the top ten causes of death worldwide.\" \/>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.embl.org\/news\/science\/tuberculosis-suicide\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Cell death trigger in tuberculosis bacteria | EMBL\" \/>\n<meta property=\"og:description\" content=\"The suicide system in tuberculosis (TB) bacteria might hold the key to the treatment of TB, one of the top ten causes of death worldwide.\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.embl.org\/news\/science\/tuberculosis-suicide\/\" \/>\n<meta property=\"og:site_name\" content=\"EMBL\" \/>\n<meta property=\"article:publisher\" content=\"https:\/\/www.facebook.com\/embl.org\/\" \/>\n<meta property=\"article:published_time\" content=\"2019-02-18T16:00:40+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2024-03-22T10:17:16+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2019\/02\/illustration_version-A.png\" \/>\n\t<meta property=\"og:image:width\" content=\"620\" \/>\n\t<meta property=\"og:image:height\" content=\"425\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/png\" \/>\n<meta name=\"author\" content=\"Iris Kruijen\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:creator\" content=\"@IrisKruijen\" \/>\n<meta name=\"twitter:site\" content=\"@embl\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Iris Kruijen\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"3 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"NewsArticle\",\"@id\":\"https:\/\/www.embl.org\/news\/science\/tuberculosis-suicide\/#article\",\"isPartOf\":{\"@id\":\"https:\/\/www.embl.org\/news\/science\/tuberculosis-suicide\/\"},\"author\":{\"name\":\"Iris Kruijen\",\"@id\":\"https:\/\/www.embl.org\/news\/#\/schema\/person\/bdd9b4c648f9ed37311c369a20ac77e1\"},\"headline\":\"Cell death trigger in tuberculosis bacteria\",\"datePublished\":\"2019-02-18T16:00:40+00:00\",\"dateModified\":\"2024-03-22T10:17:16+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\/\/www.embl.org\/news\/science\/tuberculosis-suicide\/\"},\"wordCount\":647,\"publisher\":{\"@id\":\"https:\/\/www.embl.org\/news\/#organization\"},\"image\":{\"@id\":\"https:\/\/www.embl.org\/news\/science\/tuberculosis-suicide\/#primaryimage\"},\"thumbnailUrl\":\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2019\/02\/illustration_version-A.png\",\"keywords\":[\"bacteria\",\"hamburg\",\"press release\",\"toxin\",\"tuberculosis\",\"wilmanns\"],\"articleSection\":[\"Science\",\"Science &amp; 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