{"id":63337,"date":"2023-10-17T09:31:10","date_gmt":"2023-10-17T07:31:10","guid":{"rendered":"https:\/\/www.embl.org\/news\/?p=63337"},"modified":"2024-07-23T14:35:09","modified_gmt":"2024-07-23T12:35:09","slug":"fighting-antimicrobial-resistance-with-new-drug-combinations","status":"publish","type":"post","link":"https:\/\/www.embl.org\/news\/science\/fighting-antimicrobial-resistance-with-new-drug-combinations\/","title":{"rendered":"Fighting antimicrobial resistance with new drug combinations"},"content":{"rendered":"\n<article class=\"vf-card vf-card--brand vf-card--bordered vf-u-margin__bottom--800\" default>\n  <div class=\"vf-card__content | vf-stack vf-stack--400\">\n      <h3 class=\"vf-card__heading\">\n      Summary    <\/h3>\n                <p class=\"vf-card__text\"><ul>\r\n \t<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Antimicrobial resistance is an emergent global threat that claims over a million lives annually, and some of the leading pathogens responsible for these deaths are Gram-positive bacteria<\/span><i><span style=\"font-weight: 400;\">.\u00a0<\/span><\/i><\/li>\r\n \t<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">In a new study, EMBL researchers have systematically profiled over 10,000 drug combinations for their effectiveness against common Gram-positive bacteria, including the pathogenic <\/span><i><span style=\"font-weight: 400;\">Staphylococcus aureus <\/span><\/i><span style=\"font-weight: 400;\">and <\/span><i><span style=\"font-weight: 400;\">Streptococcus pneumoniae,<\/span><\/i><span style=\"font-weight: 400;\"> and identified hundreds of new synergies.<\/span><\/li>\r\n \t<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">The researchers have made the full database of interactions available for other scientists to view and explore to search for new synergies and antagonisms.<\/span><\/li>\r\n<\/ul><\/p>\n      <\/div>\n<\/article>\n\n\n\n\n<p>Antimicrobial resistance \u2013 occurring when pathogens can survive antibiotic treatment \u2013 is one of the most rapidly emerging global public health threats today. According to <a href=\"https:\/\/www.thelancet.com\/journals\/lancet\/article\/PIIS0140-6736(21)02724-0\/\">a 2022 study<\/a>, nearly five million deaths were associated with antibiotic-resistant bacteria in 2019, with over a million deaths per year directly attributable to antimicrobial resistance.&nbsp;<\/p>\n\n\n\n<p><a href=\"https:\/\/www.nature.com\/articles\/s41564-023-01486-9\">In a new study<\/a>, researchers from the <a href=\"https:\/\/www.embl.org\/groups\/typas\/\">Typas Group<\/a> at EMBL Heidelberg have systematically profiled over 10,000 drug combinations for their effectiveness against common multidrug-resistant bacteria.<\/p>\n\n\n\n<p>&#8220;Previously, there have been studies on specific drug combinations, especially those commonly prescribed together in the clinic,&#8221; said Elisabetta Cacace, the first author of the study and former PhD student in the Typas group. \u201cHowever, we lacked systematic knowledge of how combinations of different classes of antibiotics, or combinations of antibiotics and non-antibiotic drugs, influence bacterial physiology, especially when considered independently of the host.\u201d&nbsp;<\/p>\n\n\n\n<p>Cacace, who is trained as a medical doctor and is currently a postdoc at ETH Z\u00fcrich, has been interested in antimicrobial resistance since early in her career. During her time in the Typas Group, which specialises in developing high-throughput approaches to studying bacterial interactions (with the environment or other species) and physiology, she turned her attention to the problem of understanding how antibiotics influence each other\u2019s actions on their cellular targets.&nbsp;&nbsp;<\/p>\n\n\n\n<p>Different antibiotics target different cellular structures or processes inside bacteria. They can synergise, which means their combined activity is more potent than the effect of each drug alone, but they can also antagonise each other, in which case the presence of one drug hampers the activity of another. Such antagonising interactions can be used to <a href=\"https:\/\/www.embl.org\/news\/science\/antibiotics-effects-microbiome\/\">mitigate the collateral damage of antibiotics on our gut microbiota<\/a>.<\/p>\n\n\n\n<p><a href=\"https:\/\/europepmc.org\/article\/MED\/29973719\">In a previous study<\/a>, researchers from the Typas Group had profiled drug combinations against Gram-negative bacteria \u2013 a class that includes many deadly antimicrobial-resistant pathogens, including <em>E. coli<\/em>, <em>Salmonella enterica, <\/em>and <em>Pseudomonas aeruginosa.<\/em> However, <a href=\"https:\/\/www.thelancet.com\/journals\/lancet\/article\/PIIS0140-6736(21)02724-0\/fulltext\">many deadly<\/a> antimicrobial-resistant bacteria also belong to the Gram-positive category, including <em>Staphylococcus aureus, <\/em>whose methicillin-resistant variant (MRSA) causes hundreds of thousands of deaths each year. These bacteria have a different cell wall structure to Gram-negative bacteria, which influences the activity and effectiveness of drugs.&nbsp;<\/p>\n\n\n\n<p>For the current study, the team used a sophisticated robotics set-up to simultaneously study the effects of hundreds of combinations of antibiotic and non-antibiotic drugs, across a range of doses, on three representative species of Gram-positive bacteria &#8211; <em>Bacillus subtilis, Staphylococcus aureus, and Streptococcus pneumoniae<\/em>. In addition to over 8,000 combinations of 65 different antibiotics, spread across all major classes, the researchers also profiled over 2,500 combinations of antibiotic drugs with non-antibiotic drugs, which may be co-prescribed in an age where polypharmacy \u2013 simultaneous use of multiple medications \u2013 is very common.<\/p>\n\n\n\n<p>Using this strategy, the team identified over a thousand interactions, including both synergies and antagonisms. The effects were highly species- and even strain-specific, and distinct from the interactions seen in the previous study in Gram-negative bacteria. They also validated some of these results <em>in vivo<\/em>, by infecting moth larvae with the pathogen and testing the ability of specific drug combinations to aid in recovery.&nbsp;<\/p>\n\n\n\n<p>The researchers have made the full database of interactions openly available for other scientists to view, explore, and use to search for new synergies and antagonisms.<\/p>\n\n\n\n<p>&#8220;We think the scale of this study really sets it apart. This is such a rich dataset that I think it will feed hypotheses for many years to come,&#8221; said Cacace. \u201cI also find it interesting from a systems biology perspective, because we see interactions between drugs targeting certain cellular processes that were not known before.\u201d<\/p>\n\n\n\n<p>&#8220;We are living in an era when novel strategies against antimicrobial resistance are desperately needed, and the development of new antibiotics is technically challenging, costly, and time-consuming,&#8221; said Nassos Typas, EMBL Group Leader and the study\u2019s senior author. \u201cSystematic drug interaction profiling of the kind we have performed in this study opens up the path to alternative solutions and treatments for bacterial infections.\u201d<\/p>\n\n\n\n\n\n\n\n<h1 class=\"wp-block-heading\" id=\"a1\"><strong>Nuove combinazioni di farmaci per combattere la resistenza agli antibiotici<\/strong><\/h1>\n\n\n\n<p><em>In un&#8217;indagine approfondita e su larga scala, i ricercatori dell&#8217;EMBL hanno testato oltre 10.000 combinazioni di farmaci contro alcuni batteri responsabili del numero pi\u00f9 alto di morti associate alla resistenza antimicrobica.<\/em><\/p>\n\n\n\n<article class=\"vf-card vf-card--brand vf-card--bordered vf-u-margin__bottom--800\" default>\n  <div class=\"vf-card__content | vf-stack vf-stack--400\">\n      <h3 class=\"vf-card__heading\">\n      Sommario    <\/h3>\n                <p class=\"vf-card__text\"><ul>\r\n \t<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">La resistenza antimicrobica \u00e8 una minaccia emergente a livello globale che miete oltre un milione di vittime all&#8217;anno\r\n<\/span><i><span style=\"font-weight: 400;\">.\u00a0<\/span><\/i><\/li>\r\n \t<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Un nuovo studio condotto da una ricercatrice italiana all\u2019EMBL di Heidelberg, ha analizzato in maniera sistematica oltre 10.000 combinazioni di farmaci per valutare la loro efficacia contro batteri Gram-positivi comuni, identificando centinaia di nuove interazioni.<\/span><\/li>\r\n \t<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">L\u2019intero database delle interazioni \u00e8 stato reso pubblico affinch\u00e9 altri scienziati possano esplorarlo e utilizzarlo per cercare nuove sinergie e antagonismi tra farmaci.<\/span><\/li>\r\n<\/ul><\/p>\n      <\/div>\n<\/article>\n\n\n\n\n<p>La resistenza agli antimicrobici &#8211; la capacit\u00e0 degli agenti patogeni di sopravvivere a terapie antibiotiche &#8211; \u00e8 una delle principali minacce globali emergenti. Secondo <a href=\"https:\/\/www.thelancet.com\/journals\/lancet\/article\/PIIS0140-6736(21)02724-0\/f\">uno studio del 2022<\/a>, quasi cinque milioni di decessi sono stati associati a batteri resistenti agli antibiotici nel 2019, con oltre un milione di morti direttamente attribuibili alla resistenza antimicrobica.&nbsp;<\/p>\n\n\n\n<p>In un <a href=\"https:\/\/www.nature.com\/articles\/s41564-023-01486-9#citeas\">nuovo studio<\/a> pubblicato sulla rivista Nature Microbiology, i ricercatori del laboratorio<a href=\"https:\/\/www.embl.org\/groups\/typas\/\"> di Nassos Typas<\/a> presso l&#8217;EMBL di Heidelberg hanno analizzato in maniera sistematica oltre 10.000 combinazioni di farmaci per valutare la loro efficacia contro batteri comuni resistenti ai farmaci.<\/p>\n\n\n\n<p>&#8220;In passato sono stati condotti studi su specifiche combinazioni di farmaci, in particolare su quelli comunemente prescritti insieme nella pratica clinica&#8221;, ha dichiarato Elisabetta Cacace, prima autrice dello studio ed ex dottoranda nel gruppo. &#8220;Tuttavia, il numero di combinazioni possibili tra antibiotici \u00e8 enorme e molte di queste interazioni non sono mai state testate. Inoltre, abbiamo osservato che anche i farmaci non-antibiotici possono modulare l&#8217;effetto degli antibiotici sui batteri, indipendentemente dall&#8217;ospite. Questo significa che ci sono tantissime combinazioni tra antibiotici e non-antibiotici ancora da esplorare\u201d.<\/p>\n\n\n\n<p>Cacace, medico e attualmente postdoc presso l&#8217;ETH di Zurigo, si \u00e8 interessata al problema della resistenza agli antibiotici fin dall&#8217;inizio della sua carriera. Durante il periodo trascorso nel laboratorio di Nassos Typas, specializzato nello studio su larga scala delle interazioni tra i batteri e l\u2019ambiente, si \u00e8 concentrata sulle interazioni reciproche tra antibiotici e il loro impatto sulla sopravvivenza e la resistenza dei batteri.&nbsp;&nbsp;<\/p>\n\n\n\n<p>Diversi antibiotici hanno come bersaglio diverse strutture o processi cellulari all&#8217;interno dei batteri. Quando vengono somministrati in contemporanea \u00e8 possibile che ci sia un effetto sinergico, ovvero che l\u2019efficacia combinata dei due farmaci sia pi\u00f9 forte che l\u2019efficacia di ciascun farmaco dato singolarmente. In altri casi invece pu\u00f2 esserci un\u2019azione antagonista, cio\u00e8 la presenza di un farmaco inibisce l&#8217;attivit\u00e0 di un altro. Questi effetti antagonisti possono essere usati per <a href=\"https:\/\/www.embl.org\/news\/science\/antibiotics-effects-microbiome\/\">mitigare i danni collaterali che gli antibiotici provocano al nostro microbiota<\/a>.<\/p>\n\n\n\n<p>In uno <a href=\"https:\/\/europepmc.org\/article\/MED\/29973719\">studio precedente<\/a>, i ricercatori del gruppo Typas avevano testato l\u2019efficacia di alcune combinazioni di farmaci contro i batteri Gram-negativi, una classe che comprende molti patogeni pericolosi come l&#8217;<em>Escherichia coli <\/em>e la <em>Salmonella enterica<\/em>. Tuttavia, <a href=\"https:\/\/www.thelancet.com\/journals\/lancet\/article\/PIIS0140-6736(21)02724-0\/fulltext\">molti batteri letali<\/a> resistenti agli antibiotici appartengono anche alla categoria dei Gram-positivi, tra cui lo <em>Staphylococcus aureus<\/em>, la cui variante resistente alla meticillina (MRSA) causa centinaia di migliaia di morti ogni anno. Questi batteri hanno una struttura della parete cellulare diversa da quella dei batteri Gram-negativi, che influenza l&#8217;attivit\u00e0 e l&#8217;efficacia dei farmaci.<\/p>\n\n\n\n<p>Per questo studio, il gruppo ha utilizzato un sofisticato sistema robotico in grado di analizzare simultaneamente gli effetti di centinaia di combinazioni di farmaci antibiotici e non antibiotici, a diverse concentrazioni , su tre specie rappresentative di batteri Gram-positivi &#8211; <em>Bacillus subtilis, Staphylococcus aureus, and Streptococcus pneumoniae<\/em>. Oltre a pi\u00f9 di 8.000 combinazioni di 65 antibiotici diversi, i ricercatori hanno anche testato pi\u00f9 di 2.500 combinazioni di farmaci antibiotici con farmaci comuni non antibiotici che vengono talvolta somministrati allo stesso tempo, in un\u2019era in cui la politerapia \u00e8 molto comune.&nbsp;<\/p>\n\n\n\n<p>Utilizzando questa strategia, il team ha identificato centinaia di nuove interazioni, tra cui sinergie e antagonismi. Gli effetti sono altamente specifici per specie batterica e si distinguono dalle interazioni osservate nello studio precedente sui batteri Gram-negativi. Alcuni di questi risultati sono stati confermati in vivo, infettando larve di insetto con batteri multiresistenti isolati da pazienti e testando la capacit\u00e0 di alcune combinazioni sinergiche&nbsp; di combattere l\u2019infezione.<\/p>\n\n\n\n<p>L\u2019intero database delle interazioni \u00e8 stato reso pubblico affinch\u00e9 altri scienziati possano esplorarlo e usarlo per cercare nuove sinergie e antagonismi.&#8221;Pensiamo che la scala di questo studio sia il vero elemento distintivo. Ha prodotto un insieme di dati cos\u00ec ricco che supporter\u00e0 nuove ipotesi e possibili combinazioni da testare per uso clinico per molti anni a venire&#8221;, ha detto Elisabetta Cacace. &#8220;\u00c8 interessante anche da un punto di vista di microbiologia di base e di biologia dei sistemi, perch\u00e9 le interazioni tra farmaci rispecchiano le interazioni tra i processi cellulari che i farmaci colpiscono, e molte di queste relazioni non sono mai state osservate prima&#8221;.<\/p>\n\n\n\n<p>&#8220;Viviamo in un&#8217;epoca in cui c\u2019\u00e8 un urgente bisogno di nuove strategie contro la resistenza antimicrobica, e lo sviluppo di nuovi antibiotici \u00e8 tecnicamente impegnativo, costoso e lungo&#8221;, ha dichiarato Nassos Typas, Group Leader dell&#8217;EMBL e coordinatore dello studio. &#8220;L\u2019analisi sistematica delle interazioni tra farmaci, come quella che abbiamo eseguito in questo studio, apre la strada a soluzioni e trattamenti alternativi e immediatamente disponibili per trattare le infezioni batteriche&#8221;.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>In an extensive investigation, EMBL researchers have tested over 10,000 drug combinations against some of the leading pathogenic bacteria carrying antimicrobial resistance and causing mortality.\u00a0<\/p>\n","protected":false},"author":124,"featured_media":63345,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[2,17591],"tags":[584,494,580,981,662,5776,17693,1748,582],"embl_taxonomy":[19391],"class_list":["post-63337","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-science","category-science-technology","tag-antibiotic","tag-antibiotic-resistance","tag-bacteria","tag-drug","tag-drug-combinations","tag-microbial-ecosystems","tag-molecular-systems-biology","tag-press-release","tag-typas","embl_taxonomy-typas-group"],"acf":{"vf_locked":false,"featured":true,"show_featured_image":false,"field_target_display":"embl","field_article_language":{"value":"english","label":"English"},"article_intro":"<p>In an extensive investigation, EMBL researchers have tested over 10,000 drug combinations against some of the leading pathogenic bacteria carrying antimicrobial resistance and causing mortality<\/p>\n","related_links":[{"link_description":"Typas Group\r\n","link_url":"https:\/\/www.embl.org\/groups\/typas\/"},{"link_description":"Genome Biology Unit","link_url":"https:\/\/www.embl.org\/research\/units\/genome-biology\/"},{"link_description":"Combining antibiotics changes their effectiveness\r\n","link_url":"https:\/\/www.embl.org\/news\/science\/combining-antibiotics-changes-their-effectiveness\/"}],"source_article":[{"publication_title":"Systematic analysis of drug combinations against Gram-positive bacteria","publication_link":{"title":"","url":"https:\/\/www.nature.com\/articles\/s41564-023-01486-9","target":""},"publication_authors":"Cacace E., et al","publication_source":"Nature Microbiology","publication_date":"28 September 2023","publication_doi":"10.1038\/s41564-023-01486-9"}],"in_this_article":false,"press_contact":"EMBL Generic","article_translations":[{"translation_language":"Italiano","translation_anchor":"#a1"}],"languages":""},"embl_taxonomy_terms":[{"uuid":"a:3:{i:0;s:36:\"302cfdf7-365b-462a-be65-82c7b783ebf7\";i:1;s:36:\"bd910dd7-0cda-4618-8bfa-d37fbda8438e\";i:2;s:36:\"94ddaf2b-18a5-4239-9017-bb23f22f3e9f\";}","parents":[],"name":["Typas Group"],"slug":"typas-group","description":"What &gt; Molecular Systems Biology &gt; Typas Group"}],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v26.2 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>Fighting antimicrobial resistance with new drug combinations | EMBL<\/title>\n<meta name=\"description\" content=\"In an extensive investigation, EMBL researchers have profiled over 10,000 drug combinations for their effect on Gram-positive bacteria.\" \/>\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\/fighting-antimicrobial-resistance-with-new-drug-combinations\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Fighting antimicrobial resistance with new drug combinations | EMBL\" \/>\n<meta property=\"og:description\" content=\"In an extensive investigation, EMBL researchers have profiled over 10,000 drug combinations for their effect on Gram-positive bacteria.\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.embl.org\/news\/science\/fighting-antimicrobial-resistance-with-new-drug-combinations\/\" \/>\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=\"2023-10-17T07:31:10+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2024-07-23T12:35:09+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2023\/10\/20230928_TypasAdaptation-scaled-e1697030463659.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"1000\" \/>\n\t<meta property=\"og:image:height\" content=\"600\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"author\" content=\"Shreya Ghosh\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:creator\" content=\"@embl\" \/>\n<meta name=\"twitter:site\" content=\"@embl\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Shreya Ghosh\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"7 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\/fighting-antimicrobial-resistance-with-new-drug-combinations\/#article\",\"isPartOf\":{\"@id\":\"https:\/\/www.embl.org\/news\/science\/fighting-antimicrobial-resistance-with-new-drug-combinations\/\"},\"author\":{\"name\":\"Shreya Ghosh\",\"@id\":\"https:\/\/www.embl.org\/news\/#\/schema\/person\/de071e57de42c03b5f23d1e391048fb2\"},\"headline\":\"Fighting antimicrobial resistance with new drug combinations\",\"datePublished\":\"2023-10-17T07:31:10+00:00\",\"dateModified\":\"2024-07-23T12:35:09+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\/\/www.embl.org\/news\/science\/fighting-antimicrobial-resistance-with-new-drug-combinations\/\"},\"wordCount\":1457,\"publisher\":{\"@id\":\"https:\/\/www.embl.org\/news\/#organization\"},\"image\":{\"@id\":\"https:\/\/www.embl.org\/news\/science\/fighting-antimicrobial-resistance-with-new-drug-combinations\/#primaryimage\"},\"thumbnailUrl\":\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2023\/10\/20230928_TypasAdaptation-scaled-e1697030463659.jpg\",\"keywords\":[\"antibiotic\",\"antibiotic resistance\",\"bacteria\",\"drug\",\"drug combinations\",\"microbial ecosystems\",\"molecular systems biology\",\"press release\",\"typas\"],\"articleSection\":[\"Science\",\"Science &amp; 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