{"id":1829,"date":"2013-07-12T08:59:59","date_gmt":"2013-07-12T07:59:59","guid":{"rendered":"https:\/\/blogs.ncl.ac.uk\/icamblog\/?p=1829"},"modified":"2013-09-15T14:16:44","modified_gmt":"2013-09-15T13:16:44","slug":"a-tail-to-tell-lakey-lab-discovery-could-lead-to-a-new-class-of-antibiotics","status":"publish","type":"post","link":"https:\/\/blogs.ncl.ac.uk\/icamblog\/a-tail-to-tell-lakey-lab-discovery-could-lead-to-a-new-class-of-antibiotics\/","title":{"rendered":"A &#8216;tail&#8217; to tell &#8211; Lakey lab discovery could lead to a new class of antibiotics"},"content":{"rendered":"<p>&nbsp;<\/p>\n<div id=\"attachment_1856\" style=\"width: 210px\" class=\"wp-caption alignright\"><a href=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/a-tail-to-tell-lakey-lab-discovery-could-lead-to-a-new-class-of-antibiotics\/chris-4\/\" rel=\"attachment wp-att-1856\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-1856\" class=\" wp-image-1856    \" src=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/files\/2013\/07\/Chris3-250x300.jpg\" alt=\"\" width=\"200\" height=\"240\" srcset=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/files\/2013\/07\/Chris3-250x300.jpg 250w, https:\/\/blogs.ncl.ac.uk\/icamblog\/files\/2013\/07\/Chris3.jpg 440w\" sizes=\"auto, (max-width: 200px) 100vw, 200px\" \/><\/a><p id=\"caption-attachment-1856\" class=\"wp-caption-text\">Dr Chris Johnson<\/p><\/div>\n<p><em>&#8220;Most of us know that we should wash our hands after being around animals but do most of us know the reasons why? As a researcher who spends most of his time in the lab killing<\/em><em>\u00a0<\/em><a href=\"https:\/\/en.wikipedia.org\/wiki\/Escherichia_coli\" target=\"_blank\">E. coli<\/a><em>, using<\/em><em>\u00a0<\/em>E. coli<em>\u00a0<\/em><em>specific antibiotics I should be well aware of the dangers of this often underestimated Gram-negative bacteria. However when my youngest daughter contracted<\/em><em>\u00a0<\/em><a href=\"http:\/\/www.hse.gov.uk\/campaigns\/farmsafe\/ecoli.htm\" target=\"_blank\">E. coli<em>\u00a0<\/em><\/a><em><a href=\"http:\/\/www.hse.gov.uk\/campaigns\/farmsafe\/ecoli.htm\" target=\"_blank\">O157<\/a> after visiting an agricultural show in Scotland in 2011 (even though we had followed the hand washing procedure), I realised that I did not appreciate how nasty this bacteria can be. Thankfully after 6 weeks in hospital including a lengthy stretch on dialysis my daughter made a full recovery but not everyone is so lucky.&#8221;<\/em><\/p>\n<div id=\"attachment_1857\" style=\"width: 202px\" class=\"wp-caption alignright\"><a href=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/a-tail-to-tell-lakey-lab-discovery-could-lead-to-a-new-class-of-antibiotics\/jeremy-3-2\/\" rel=\"attachment wp-att-1857\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-1857\" class=\"size-medium wp-image-1857\" src=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/files\/2013\/07\/Jeremy-31-192x300.jpg\" alt=\"\" width=\"192\" height=\"300\" srcset=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/files\/2013\/07\/Jeremy-31-192x300.jpg 192w, https:\/\/blogs.ncl.ac.uk\/icamblog\/files\/2013\/07\/Jeremy-31.jpg 320w\" sizes=\"auto, (max-width: 192px) 100vw, 192px\" \/><\/a><p id=\"caption-attachment-1857\" class=\"wp-caption-text\">Professor Jeremy Lakey<\/p><\/div>\n<p>The urgent need to develop new drugs to target pathogenic bacteria has been a theme of the <a href=\"http:\/\/www.ncl.ac.uk\/camb\/\" target=\"_blank\">ICaMB<\/a> blog since its inception in early 2013.\u00a0 However, these words from Dr Chris Johnson, a postdoc in <a href=\"http:\/\/www.ncl.ac.uk\/camb\/staff\/profile\/jeremy.lakey\" target=\"_blank\">Jeremy Lakey<\/a>\u2019s laboratory, bring home the seriousness of the problem.\u00a0 Fortunately, Chris is in a position to do something about this.<\/p>\n<p>Many of you will have realised that last week saw another potential breakthrough in ICaMB\u2019s ongoing \u2018<a href=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/exploding-bacteria-for-science\/\" target=\"_blank\">War on bacteria<\/a>\u2019 (and <a href=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/bulging-bacteria-and-life-origins\/\" target=\"_blank\">here<\/a>, <a href=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/icamb-research-update-zenkin-lab-science-paper\/\" target=\"_blank\">here<\/a> and <a href=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/spills-and-pills-thrills-for-a-structural-biologist\/\" target=\"_blank\">here<\/a>).\u00a0\u00a0 This time the PI making the news, with data demonstrating the possibility of a whole new class of antibiotics, was <a href=\"http:\/\/www.ncl.ac.uk\/camb\/staff\/profile\/jeremy.lakey\" target=\"_blank\">Professor Jeremy Lakey<\/a>.\u00a0 And when we say making the news, we mean that literally. The <a href=\"http:\/\/www.itv.com\/news\/tyne-tees\/story\/2013-07-05\/breakthrough-in-combatting-bacterial-infection\/\" target=\"_blank\">ITV interview<\/a> of Jeremy and his team can be viewed here<\/p>\n<p><iframe loading=\"lazy\" title=\"New bacteria killer molecule - Prof Lakey on ITVNews Tyneside\" width=\"584\" height=\"329\" src=\"\/\/www.youtube.com\/embed\/_dWoD8peVA0?feature=oembed\" frameborder=\"0\" allow=\"accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share\" referrerpolicy=\"strict-origin-when-cross-origin\" allowfullscreen><\/iframe><\/p>\n<p>This story has made news around the world and has been featured in newspapers in\u00a0<a href=\"http:\/\/www.theaustralian.com.au\/news\/breaking-news\/tail-could-be-used-for-new-drugs\/story-fn3dxix6-1226674131684\">Australia<\/a> and <a href=\"http:\/\/articles.timesofindia.indiatimes.com\/2013-07-06\/science\/40406695_1_escherichia-coli-e-coli-protein\" target=\"_blank\">India<\/a>\u00a0(and <a href=\"http:\/\/www.deccanherald.com\/content\/343144\/scientists-chance-protein-can-kill.html\" target=\"_blank\">here<\/a>), as well as closer to <a href=\"http:\/\/www.thenorthernecho.co.uk\/news\/10524003.Scientists__chance_find_may_develop_new_generation_of_antibiotics\/\" target=\"_blank\">home<\/a>.\u00a0 Here is the official <a href=\"http:\/\/www.ncl.ac.uk\/press.office\/press.release\/item\/chance-finding-could-lead-to-new-antibiotics\" target=\"_blank\">university press release<\/a>.<\/p>\n<p>So what\u2019s going on?\u00a0 If you want to read the primary paper it is here<\/p>\n<p><a href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/mmi.12260\/abstract;jsessionid=6D5A4792A4027D50ED1332E6FD35AA38.d01t01\" target=\"_blank\"><strong>The unstructured domain of colicin N kills<\/strong><strong>\u00a0<\/strong><em><strong>Escherichia coli<\/strong><\/em><strong>. Mol Micro 89:84-95<\/strong><\/a><\/p>\n<p>Chris Johnson, who was the lead author on this manuscript explains:<\/p>\n<p><em>&#8220;<\/em>E. coli<em>\u00a0<\/em><em>produces protein antibiotics called <a href=\"http:\/\/en.wikipedia.org\/wiki\/Colicin\" target=\"_blank\">colicins<\/a> which are used to kill<\/em><em>\u00a0<\/em>E. coli<em>\u00a0<\/em><em>and closely \u00a0related bacteria in the eternal bacterial arms race. In order to further<em>\u00a0<\/em>understand how\u00a0<em>one of these, colicin N (ColN), works,<\/em>\u00a0we dissected the protein into its individual domains to see how each part behaved in isolation. Quite by chance we found that part of the protein, THE TAIL, was actually toxic to them. Although far less efficient than the entire ColN molecule, it remains specific for<\/em><em>\u00a0<\/em>E. coli<em>\u00a0<\/em><em>and furthermore, the specificity is housed within an intrinsically unfolded domain (a domain which has no defined 3D structure). Although this is a very basic discovery in its early stages, it allows us to appreciate novel mechanisms to kill<\/em><em>\u00a0<\/em>E. coli<em>.\u201d (see the full version of this at the bottom of the page)<\/em><\/p>\n<p><strong>Some more about Jeremy<\/strong><\/p>\n<p><a href=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/a-tail-to-tell-lakey-lab-discovery-could-lead-to-a-new-class-of-antibiotics\/jeremy-4\/\" rel=\"attachment wp-att-1879\"><img loading=\"lazy\" decoding=\"async\" class=\"alignright size-medium wp-image-1879\" src=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/files\/2013\/07\/Jeremy-4-300x199.jpg\" alt=\"\" width=\"300\" height=\"199\" srcset=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/files\/2013\/07\/Jeremy-4-300x199.jpg 300w, https:\/\/blogs.ncl.ac.uk\/icamblog\/files\/2013\/07\/Jeremy-4-450x300.jpg 450w, https:\/\/blogs.ncl.ac.uk\/icamblog\/files\/2013\/07\/Jeremy-4.jpg 1024w\" sizes=\"auto, (max-width: 300px) 100vw, 300px\" \/><\/a>Any of you who were bioscience undergraduates in Newcastle will know Jeremy Lakey from his famous recreations of protein structure using party balloons.\u00a0\u00a0Others may know him for co-founding <a href=\"http:\/\/www.orlaproteins.com\/about-orla\/the-board.aspx\" target=\"_blank\">Orla Protein technologies<\/a>.\u00a0\u00a0Some of us know him as a man who will always buy his round in the pub.\u00a0\u00a0All of us know him <a href=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/a-tail-to-tell-lakey-lab-discovery-could-lead-to-a-new-class-of-antibiotics\/lego-2\/\" rel=\"attachment wp-att-1881\"><img loading=\"lazy\" decoding=\"async\" class=\"alignright size-medium wp-image-1881\" src=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/files\/2013\/07\/Lego1-300x225.jpg\" alt=\"\" width=\"300\" height=\"225\" srcset=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/files\/2013\/07\/Lego1-300x225.jpg 300w, https:\/\/blogs.ncl.ac.uk\/icamblog\/files\/2013\/07\/Lego1-400x300.jpg 400w, https:\/\/blogs.ncl.ac.uk\/icamblog\/files\/2013\/07\/Lego1.jpg 640w\" sizes=\"auto, (max-width: 300px) 100vw, 300px\" \/><\/a>as a great scientist and colleague.\u00a0\u00a0Furthermore, Jeremy is a leading supporter of <a href=\"https:\/\/blogs.ncl.ac.uk\/leadingedge\">Leading Edge<\/a>\u00a0and recently a group of 6 Year 9 school pupils from\u00a0<a href=\"http:\/\/www.st-cuthbertshigh.newcastle.sch.uk\/\">St Cuthberts RC School<\/a>\u00a0looked at how ColN acts against\u00a0<em>E.coli<\/em>\u00a0when you start changing the amount of salt they are grown in. As many ICaMB scientists may know Jeremy also runs a workshop with\u00a0<a href=\"http:\/\/ponthigh.org.uk\/\">Ponteland Community High School<\/a>\u00a0to explore bacterial shape and their surfaces using LEGO.<\/p>\n<p>But did any of us think that one day Jeremy Lakey may SAVE THE WORLD from antibiotic resistant bacteria? Possibly.<\/p>\n<p><strong>The detailed science <\/strong><\/p>\n<p><em>Most Gram- negative bacteria produce protein antibiotics which are used as weapons in the battle between competing populations of bacteria.\u00a0 E. coli produces protein antibiotics called colicins which are use to kill E. coli and closely related bacteria.\u00a0 Once colicins are released into the extracellular milleu they dock onto their targets via specific outer-membrane receptors and then seek out an internal, periplasmic, binding partner (the Tol or Ton proteins) which helps them translocate into the cell.\u00a0 We study colicin N (ColN) which comprises of an intrinsically unfolded N-terminal translocation (T) domain, involved in TolA and OmpF binding.\u00a0 Its central receptor binding (R) domain binds lipopolysaccharide whilst its C-terminal 200 amino acids define the cytotoxic pore-forming (P) domain. This latter feature is common to all pore-forming colicins and forms a channel in the inner-membrane causing K<sup>+<\/sup> release and cell death.\u00a0 Other colicins have C-terminal domains which display cytotoxic activities that include DNAase or RNase activity.\u00a0 Irrespective of the particular cytotoxic activity, all colicins are comprised of three domains (T-R-P) and it was assumed that the sole role of the T and R domains was to deliver the cytotoxic C-terminal domain across the outer-membrane. <\/em><strong><\/strong><\/p>\n<p><em><a href=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/a-tail-to-tell-lakey-lab-discovery-could-lead-to-a-new-class-of-antibiotics\/colicin\/\" rel=\"attachment wp-att-1870\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter size-full wp-image-1870\" src=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/files\/2013\/07\/Colicin.jpg\" alt=\"\" width=\"699\" height=\"503\" srcset=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/files\/2013\/07\/Colicin.jpg 699w, https:\/\/blogs.ncl.ac.uk\/icamblog\/files\/2013\/07\/Colicin-300x215.jpg 300w, https:\/\/blogs.ncl.ac.uk\/icamblog\/files\/2013\/07\/Colicin-416x300.jpg 416w\" sizes=\"auto, (max-width: 699px) 100vw, 699px\" \/><\/a>In order to investigate the mechanism of ColN activity we dissected the protein into its individual domains.\u00a0 We were attempting to block the toxic activity of full length ColN by pre- incubating E. coli cells with the intrinsically unfolded T-domain.\u00a0 The rationale behind the experiment was that we could block all the available receptor sites on the E. coli target cells by saturating with T-domain, such that when the full length ColN was added to cells it would be non-toxic, as all the essential receptor binding sites would be already sequestered.\u00a0 However rather than protecting the cells, T-domain was found to be toxic and like full length ColN provoked K+ efflux.\u00a0\u00a0 Although less efficient than full length ColN, T-domain is strictly dependent upon the same receptor proteins, OmpF and TolA for killing.\u00a0 Since these receptors are only found in E. coli-like bacteria, T-domain displays the unusual combination of a generic killing mechanism coupled with extreme specificity housed within an intrinsically unfolded domain. <\/em><\/p>\n<p><em>Links<\/em><\/p>\n<p><em>Jeremy Lakey&#8217;s University home page<\/em>:\u00a0<a href=\"http:\/\/www.ncl.ac.uk\/camb\/staff\/profile\/jeremy.lakey\" target=\"_blank\">http:\/\/www.ncl.ac.uk\/camb\/staff\/profile\/jeremy.lakey<\/a><\/p>\n<p><em>Follow Jeremy Lakey on Twitter<\/em>:\u00a0<a href=\"https:\/\/twitter.com\/JeremyLakey\" target=\"_blank\">https:\/\/twitter.com\/JeremyLakey<\/a><\/p>\n<p><em>ICaMB<\/em>:\u00a0<a href=\"http:\/\/www.ncl.ac.uk\/camb\/\" target=\"_blank\">http:\/\/www.ncl.ac.uk\/camb\/<\/a><\/p>\n<p><em>The Centre for Bacterial cell Biology<\/em>:\u00a0<a href=\"http:\/\/www.ncl.ac.uk\/cbcb\/\" target=\"_blank\">http:\/\/www.ncl.ac.uk\/cbcb\/<\/a><\/p>\n<p><em>The official Newcastle University press release:\u00a0<a href=\"http:\/\/www.ncl.ac.uk\/press.office\/press.release\/item\/chance-finding-could-lead-to-new-antibiotics\">http:\/\/www.ncl.ac.uk\/press.office\/press.release\/item\/chance-finding-could-lead-to-new-antibiotics<\/a><\/em><\/p>\n<p><em>Link to ITV story<\/em>:<\/p>\n<p><a href=\"http:\/\/www.itv.com\/news\/tyne-tees\/story\/2013-07-05\/breakthrough-in-combatting-bacterial-infection\/\">http:\/\/www.itv.com\/news\/tyne-tees\/story\/2013-07-05\/breakthrough-in-combatting-bacterial-infection\/<\/a><\/p>\n<p><em>The &#8216;Australian&#8217; story<\/em>:\u00a0<a href=\"http:\/\/www.theaustralian.com.au\/news\/breaking-news\/tail-could-be-used-for-new-drugs\/story-fn3dxix6-1226674131684\" target=\"_blank\">http:\/\/www.theaustralian.com.au\/news\/breaking-news\/tail-could-be-used-for-new-drugs\/story-fn3dxix6-1226674131684<\/a><\/p>\n<p><em>The &#8216;Times of India&#8217; Story<\/em>:\u00a0<a href=\"http:\/\/articles.timesofindia.indiatimes.com\/2013-07-06\/science\/40406695_1_escherichia-coli-e-coli-protein\" target=\"_blank\">http:\/\/articles.timesofindia.indiatimes.com\/2013-07-06\/science\/40406695_1_escherichia-coli-e-coli-protein<\/a><\/p>\n<p><em>The Northern Echo story<\/em>:\u00a0<a href=\"http:\/\/www.thenorthernecho.co.uk\/news\/10524003.Scientists__chance_find_may_develop_new_generation_of_antibiotics\/\" target=\"_blank\">http:\/\/www.thenorthernecho.co.uk\/news\/10524003.Scientists__chance_find_may_develop_new_generation_of_antibiotics\/<\/a><\/p>\n<p><em>Jeremy&#8217;s company, Orla Proteins<\/em>:\u00a0<a href=\"http:\/\/www.orlaproteins.com\/about-orla\/the-board.aspx\">http:\/\/www.orlaproteins.com\/about-orla\/the-board.aspx<\/a><em><\/em><\/p>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>&nbsp; &#8220;Most of us know that we should wash our hands after being around animals but do most of us know the reasons why? As a researcher who spends most of his time in the lab killing\u00a0E. coli, using\u00a0E. coli\u00a0specific &hellip; <a href=\"https:\/\/blogs.ncl.ac.uk\/icamblog\/a-tail-to-tell-lakey-lab-discovery-could-lead-to-a-new-class-of-antibiotics\/\">Continue reading <span class=\"meta-nav\">&rarr;<\/span><\/a><\/p>\n","protected":false},"author":1713,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[7,8],"tags":[43,11],"class_list":["post-1829","post","type-post","status-publish","format-standard","hentry","category-research","category-papers","tag-antibiotics","tag-bacteria"],"_links":{"self":[{"href":"https:\/\/blogs.ncl.ac.uk\/icamblog\/wp-json\/wp\/v2\/posts\/1829","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/blogs.ncl.ac.uk\/icamblog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blogs.ncl.ac.uk\/icamblog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blogs.ncl.ac.uk\/icamblog\/wp-json\/wp\/v2\/users\/1713"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.ncl.ac.uk\/icamblog\/wp-json\/wp\/v2\/comments?post=1829"}],"version-history":[{"count":59,"href":"https:\/\/blogs.ncl.ac.uk\/icamblog\/wp-json\/wp\/v2\/posts\/1829\/revisions"}],"predecessor-version":[{"id":1900,"href":"https:\/\/blogs.ncl.ac.uk\/icamblog\/wp-json\/wp\/v2\/posts\/1829\/revisions\/1900"}],"wp:attachment":[{"href":"https:\/\/blogs.ncl.ac.uk\/icamblog\/wp-json\/wp\/v2\/media?parent=1829"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.ncl.ac.uk\/icamblog\/wp-json\/wp\/v2\/categories?post=1829"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.ncl.ac.uk\/icamblog\/wp-json\/wp\/v2\/tags?post=1829"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}