/ en Wed, 28 May 25 09:00:00 -0400 /news/making-antibiotics-more-potent-against-drug-resistant-bacteria <span class="field field--name-title field--type-string field--label-hidden"><h1>Making antibiotics more potent against drug-resistant bacteria</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Allessandra DiCorato</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2025-05-28T09:00:00-04:00" class="datetime">May 28, 2025</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Making antibiotics more potent against drug-resistant bacteria</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Scientists find combinations of known antibiotics and other molecules that, together, have greater bacteria-killing power.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Allessandra DiCorato </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2025-05-28T09:00:00-04:00" title="Wednesday, May 28, 2025 - 09:00" class="datetime">May 28, 2025</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/p_aeruginosa_main.png?itok=kGsZgTvT 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/p_aeruginosa_main.png?itok=kGsZgTvT 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/p_aeruginosa_main.png?itok=-8trp1oA 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"/> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/p_aeruginosa_main.png?itok=PwinDE1N 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"/> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/p_aeruginosa_main.png?itok=XKyhkUVZ 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"/> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/p_aeruginosa_main.png?itok=gUqS-cB5 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"/> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/p_aeruginosa_main.png?itok=gUqS-cB5" alt="illustration showing pink bacteria on a blue background" title="illustration showing pink bacteria on a blue background" typeof="foaf:Image" /> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Medical Illustrator: Jennifer Oosthuizen </div> <div class="media-caption__description"> An illustration depicting Pseudomonas aeruginosa bacteria, which are multi-drug resistant. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous" /></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/599/feed&title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#facebook" /> </svg> </a> <a href="https://twitter.com/intent/tweet?text=+/taxonomy/term/599/feed" target="_blank" title="Share to X" aria-label="Share to X" class="social-sharing-buttons-button share-x" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#x" /> </svg> </a> <a href="mailto:?subject=&body=/taxonomy/term/599/feed" title="Share to Email" aria-label="Share to Email" class="social-sharing-buttons-button share-email" target="_blank" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-narrow paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Researchers have created a pipeline for discovering unique combinations of molecules that increase the effectiveness of antibiotics against drug-resistant bacteria. The team, led by scientists at the ӳ����ý and the Tufts University School of Medicine, used a microfluidic approach to screen more than 1 million combinations of antibiotics, small molecules, and bacteria. They identified a small molecule that boosts the power of the antibiotic rifampin in certain bacteria by weakening their defenses. The team also developed another molecule that was even more potent. </p> <p>The findings were recently published in <em><a href="https://www.pnas.org/doi/10.1073/pnas.2402017122" target="_blank">PNAS</a></em> and come from the Center for Innovation to Transform Antibiotic Discovery (<a href="https://reporter.nih.gov/search/fNL_12Nusky7tnR9NlUwQA/project-details/10670154" target="_blank">CITADel</a>) at the ӳ����ý and MIT. CITADel aims to accelerate discovery of antibiotics against Gram-negative bacteria that can be particularly difficult to treat and often develop resistance.</p> <p><a href="/node/7575">Paul Blainey</a>, core member of the ӳ����ý and a professor of biological engineering at MIT, was a co-senior author on the study along with <a href="https://medicine.tufts.edu/people/faculty/ralph-isberg" target="_blank">Ralph Isberg</a>, a professor at the Tufts University School of Medicine. Joan Mecsas and Bree Aldridge, both from Tufts, and CITADel leaders <a href="/node/7600">Deb Hung</a>, ӳ����ý core institute member, and <a href="/node/446076">Laura Kiessling</a>, ӳ����ý institute member, also helped drive the work.</p> <h2>ESKAPE route</h2> <p>More than 1 million people die of antibiotic-resistant infections every year and doctors need new ways to treat these patients. None of the antibiotics discovered in the last 10 years kill bacteria through new mechanisms, and it is likely that bacteria will evolve to resist these newer treatments through existing resistance mechanisms. One potential approach to addressing this is to identify other molecules, called adjuvants, that can make bacteria more susceptible to existing antibiotics.</p> <p>“A novel adjuvant could really help us overcome resistance mechanisms and better address the antibiotic crisis,” said Megan Tse, who is a co-first author on the study along with Meilin Zhu. Both Tse and Zhu were graduate students in Blainey’s lab when the work began. </p> <p>Tse, Zhu, and their team wanted to use a combinatorial approach to treat so-called “ESKAPE” pathogens, a priority designation by the World Health Organization that includes <em>Klebsiella pneumoniae</em>, <em>Acinetobacter baumannii</em>, and <em>Pseudomonas aeruginosa</em>. In their new study, the scientists focused on these three Gram-negative bacteria. </p> <p>While it might be straightforward to test a single compound against a bacterial species, testing millions of combinations of molecules quickly becomes an “absurdly large” problem requiring specialized equipment, Tse says. </p> <p>So the team turned to a technology called <a href="https://www.pnas.org/doi/full/10.1073/pnas.1802233115" target="_blank">DropArray</a>, developed by Blainey’s lab in 2018. This technique uses microarrays of hundreds of thousands of wells to combine bacteria and compounds in thousands of nanoliter-sized droplets. Fluorescent barcodes mark the precise combination in each droplet. The researchers then use a microscope to track the growth of bacteria in each well, looking for wells where bacteria don’t grow at all due to an effective combination of bacterial-killing molecules. </p> <p>To identify molecules that might help target ESKAPE pathogens, Tse, Zhu, and their colleagues scaled up the approach to analyze a panel of six bacteria, 22 known antibiotics at different concentrations, and 30,000 chemical compounds — testing about 1.3 million combinations in just one month. The team looked for molecules that had effects in multiple species.</p> <p>One compound, a molecule called P2-56, stood out. It made multiple antibiotics more effective in <em>A. baumannii</em> and <em>K. pneumoniae</em> and at least one antibiotic more effective in all of the ESKAPE species. The team also developed a more potent version of the molecule called P2-56-3 that made the antibiotic rifampin even more effective.</p> <h2>Membrane disruption</h2> <p>In additional experiments, Tse working in collaboration with Isberg lab members found that P2-56-3 disrupts the outer membrane of <em>A. baumannii</em>’s cell envelope, potentially by disrupting lipooligosaccharide transport. This may increase the bacteria’s ability to take up antibiotics such as rifampin that don’t normally enter the cell.</p> <p>Additional work is needed to determine whether P2-56-3 and rifampin could be a viable combination therapy in people. But Blainey says their technology makes possible a previously inaccessible goal of large-scale combination screening. He hopes other groups will use his team’s dataset to interpret their own results and train new computational models to predict antibiotic activity.</p> <p>“We’ve shown that with this technology and throughput, combination screening is a doable thing,” Blainey said. “I hope this expands people’s imaginations of what can be done.”</p> <p><iframe allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen frameborder="0" height="315" src="https://www.youtube.com/embed/l8NkGTSt0Ks?si=sZ_WacO1CAXO0pq2" title="YouTube video player" width="560"></iframe></p> <p><em>A video about the original DropArray technique, a tool for identifying compounds that improve the efficacy of antibiotics against bacteria.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>This work was supported in part by the National Institutes of Health, the Merkin Institute for Transformative Technologies in Healthcare, the Koch Institute for Integrative Cancer Research at MIT, and the Defense Advanced Research Projects Agency.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Tse M W, Zhu M et al. <a href="https://www.pnas.org/doi/10.1073/pnas.2402017122" target="_blank">Massively parallel combination screen reveals small molecule sensitization of antibiotic-resistant Gram-negative <em>ESKAPE</em> pathogens</a>. PNAS. Online March 24, 2025. DOI: 10.1073/pnas.2402017122.</p> <p>  </p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/blainey-lab" hreflang="en">Blainey Lab</a></div> </div> </div> </div> </div> </div> Wed, 28 May 2025 13:00:00 +0000 adicorat 5558741 at /news/surprising-new-role-major-immune-regulator <span class="field field--name-title field--type-string field--label-hidden"><h1>Making antibiotics more potent against drug-resistant bacteria</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Allessandra DiCorato</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2025-05-28T09:00:00-04:00" class="datetime">May 28, 2025</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Making antibiotics more potent against drug-resistant bacteria</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Scientists find combinations of known antibiotics and other molecules that, together, have greater bacteria-killing power.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Allessandra DiCorato </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2025-05-28T09:00:00-04:00" title="Wednesday, May 28, 2025 - 09:00" class="datetime">May 28, 2025</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/p_aeruginosa_main.png?itok=kGsZgTvT 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/p_aeruginosa_main.png?itok=kGsZgTvT 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/p_aeruginosa_main.png?itok=-8trp1oA 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"/> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/p_aeruginosa_main.png?itok=PwinDE1N 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"/> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/p_aeruginosa_main.png?itok=XKyhkUVZ 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"/> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/p_aeruginosa_main.png?itok=gUqS-cB5 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"/> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/p_aeruginosa_main.png?itok=gUqS-cB5" alt="illustration showing pink bacteria on a blue background" title="illustration showing pink bacteria on a blue background" typeof="foaf:Image" /> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Medical Illustrator: Jennifer Oosthuizen </div> <div class="media-caption__description"> An illustration depicting Pseudomonas aeruginosa bacteria, which are multi-drug resistant. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous" /></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/599/feed&title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#facebook" /> </svg> </a> <a href="https://twitter.com/intent/tweet?text=+/taxonomy/term/599/feed" target="_blank" title="Share to X" aria-label="Share to X" class="social-sharing-buttons-button share-x" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#x" /> </svg> </a> <a href="mailto:?subject=&body=/taxonomy/term/599/feed" title="Share to Email" aria-label="Share to Email" class="social-sharing-buttons-button share-email" target="_blank" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-narrow paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Researchers have created a pipeline for discovering unique combinations of molecules that increase the effectiveness of antibiotics against drug-resistant bacteria. The team, led by scientists at the ӳ����ý and the Tufts University School of Medicine, used a microfluidic approach to screen more than 1 million combinations of antibiotics, small molecules, and bacteria. They identified a small molecule that boosts the power of the antibiotic rifampin in certain bacteria by weakening their defenses. The team also developed another molecule that was even more potent. </p> <p>The findings were recently published in <em><a href="https://www.pnas.org/doi/10.1073/pnas.2402017122" target="_blank">PNAS</a></em> and come from the Center for Innovation to Transform Antibiotic Discovery (<a href="https://reporter.nih.gov/search/fNL_12Nusky7tnR9NlUwQA/project-details/10670154" target="_blank">CITADel</a>) at the ӳ����ý and MIT. CITADel aims to accelerate discovery of antibiotics against Gram-negative bacteria that can be particularly difficult to treat and often develop resistance.</p> <p><a href="/node/7575">Paul Blainey</a>, core member of the ӳ����ý and a professor of biological engineering at MIT, was a co-senior author on the study along with <a href="https://medicine.tufts.edu/people/faculty/ralph-isberg" target="_blank">Ralph Isberg</a>, a professor at the Tufts University School of Medicine. Joan Mecsas and Bree Aldridge, both from Tufts, and CITADel leaders <a href="/node/7600">Deb Hung</a>, ӳ����ý core institute member, and <a href="/node/446076">Laura Kiessling</a>, ӳ����ý institute member, also helped drive the work.</p> <h2>ESKAPE route</h2> <p>More than 1 million people die of antibiotic-resistant infections every year and doctors need new ways to treat these patients. None of the antibiotics discovered in the last 10 years kill bacteria through new mechanisms, and it is likely that bacteria will evolve to resist these newer treatments through existing resistance mechanisms. One potential approach to addressing this is to identify other molecules, called adjuvants, that can make bacteria more susceptible to existing antibiotics.</p> <p>“A novel adjuvant could really help us overcome resistance mechanisms and better address the antibiotic crisis,” said Megan Tse, who is a co-first author on the study along with Meilin Zhu. Both Tse and Zhu were graduate students in Blainey’s lab when the work began. </p> <p>Tse, Zhu, and their team wanted to use a combinatorial approach to treat so-called “ESKAPE” pathogens, a priority designation by the World Health Organization that includes <em>Klebsiella pneumoniae</em>, <em>Acinetobacter baumannii</em>, and <em>Pseudomonas aeruginosa</em>. In their new study, the scientists focused on these three Gram-negative bacteria. </p> <p>While it might be straightforward to test a single compound against a bacterial species, testing millions of combinations of molecules quickly becomes an “absurdly large” problem requiring specialized equipment, Tse says. </p> <p>So the team turned to a technology called <a href="https://www.pnas.org/doi/full/10.1073/pnas.1802233115" target="_blank">DropArray</a>, developed by Blainey’s lab in 2018. This technique uses microarrays of hundreds of thousands of wells to combine bacteria and compounds in thousands of nanoliter-sized droplets. Fluorescent barcodes mark the precise combination in each droplet. The researchers then use a microscope to track the growth of bacteria in each well, looking for wells where bacteria don’t grow at all due to an effective combination of bacterial-killing molecules. </p> <p>To identify molecules that might help target ESKAPE pathogens, Tse, Zhu, and their colleagues scaled up the approach to analyze a panel of six bacteria, 22 known antibiotics at different concentrations, and 30,000 chemical compounds — testing about 1.3 million combinations in just one month. The team looked for molecules that had effects in multiple species.</p> <p>One compound, a molecule called P2-56, stood out. It made multiple antibiotics more effective in <em>A. baumannii</em> and <em>K. pneumoniae</em> and at least one antibiotic more effective in all of the ESKAPE species. The team also developed a more potent version of the molecule called P2-56-3 that made the antibiotic rifampin even more effective.</p> <h2>Membrane disruption</h2> <p>In additional experiments, Tse working in collaboration with Isberg lab members found that P2-56-3 disrupts the outer membrane of <em>A. baumannii</em>’s cell envelope, potentially by disrupting lipooligosaccharide transport. This may increase the bacteria’s ability to take up antibiotics such as rifampin that don’t normally enter the cell.</p> <p>Additional work is needed to determine whether P2-56-3 and rifampin could be a viable combination therapy in people. But Blainey says their technology makes possible a previously inaccessible goal of large-scale combination screening. He hopes other groups will use his team’s dataset to interpret their own results and train new computational models to predict antibiotic activity.</p> <p>“We’ve shown that with this technology and throughput, combination screening is a doable thing,” Blainey said. “I hope this expands people’s imaginations of what can be done.”</p> <p><iframe allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen frameborder="0" height="315" src="https://www.youtube.com/embed/l8NkGTSt0Ks?si=sZ_WacO1CAXO0pq2" title="YouTube video player" width="560"></iframe></p> <p><em>A video about the original DropArray technique, a tool for identifying compounds that improve the efficacy of antibiotics against bacteria.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>This work was supported in part by the National Institutes of Health, the Merkin Institute for Transformative Technologies in Healthcare, the Koch Institute for Integrative Cancer Research at MIT, and the Defense Advanced Research Projects Agency.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Tse M W, Zhu M et al. <a href="https://www.pnas.org/doi/10.1073/pnas.2402017122" target="_blank">Massively parallel combination screen reveals small molecule sensitization of antibiotic-resistant Gram-negative <em>ESKAPE</em> pathogens</a>. PNAS. Online March 24, 2025. DOI: 10.1073/pnas.2402017122.</p> <p>  </p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/blainey-lab" hreflang="en">Blainey Lab</a></div> </div> </div> </div> </div> </div> Mon, 07 Aug 2023 15:02:56 +0000 tulrich@broadinstitute.org 1282656 at /news/scientists-unveil-functional-landscape-essential-genes <span class="field field--name-title field--type-string field--label-hidden"><h1>Making antibiotics more potent against drug-resistant bacteria</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Allessandra DiCorato</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2025-05-28T09:00:00-04:00" class="datetime">May 28, 2025</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Making antibiotics more potent against drug-resistant bacteria</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Scientists find combinations of known antibiotics and other molecules that, together, have greater bacteria-killing power.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Allessandra DiCorato </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2025-05-28T09:00:00-04:00" title="Wednesday, May 28, 2025 - 09:00" class="datetime">May 28, 2025</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/p_aeruginosa_main.png?itok=kGsZgTvT 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/p_aeruginosa_main.png?itok=kGsZgTvT 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/p_aeruginosa_main.png?itok=-8trp1oA 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"/> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/p_aeruginosa_main.png?itok=PwinDE1N 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"/> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/p_aeruginosa_main.png?itok=XKyhkUVZ 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"/> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/p_aeruginosa_main.png?itok=gUqS-cB5 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"/> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/p_aeruginosa_main.png?itok=gUqS-cB5" alt="illustration showing pink bacteria on a blue background" title="illustration showing pink bacteria on a blue background" typeof="foaf:Image" /> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Medical Illustrator: Jennifer Oosthuizen </div> <div class="media-caption__description"> An illustration depicting Pseudomonas aeruginosa bacteria, which are multi-drug resistant. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous" /></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/599/feed&title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#facebook" /> </svg> </a> <a href="https://twitter.com/intent/tweet?text=+/taxonomy/term/599/feed" target="_blank" title="Share to X" aria-label="Share to X" class="social-sharing-buttons-button share-x" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#x" /> </svg> </a> <a href="mailto:?subject=&body=/taxonomy/term/599/feed" title="Share to Email" aria-label="Share to Email" class="social-sharing-buttons-button share-email" target="_blank" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-narrow paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Researchers have created a pipeline for discovering unique combinations of molecules that increase the effectiveness of antibiotics against drug-resistant bacteria. The team, led by scientists at the ӳ����ý and the Tufts University School of Medicine, used a microfluidic approach to screen more than 1 million combinations of antibiotics, small molecules, and bacteria. They identified a small molecule that boosts the power of the antibiotic rifampin in certain bacteria by weakening their defenses. The team also developed another molecule that was even more potent. </p> <p>The findings were recently published in <em><a href="https://www.pnas.org/doi/10.1073/pnas.2402017122" target="_blank">PNAS</a></em> and come from the Center for Innovation to Transform Antibiotic Discovery (<a href="https://reporter.nih.gov/search/fNL_12Nusky7tnR9NlUwQA/project-details/10670154" target="_blank">CITADel</a>) at the ӳ����ý and MIT. CITADel aims to accelerate discovery of antibiotics against Gram-negative bacteria that can be particularly difficult to treat and often develop resistance.</p> <p><a href="/node/7575">Paul Blainey</a>, core member of the ӳ����ý and a professor of biological engineering at MIT, was a co-senior author on the study along with <a href="https://medicine.tufts.edu/people/faculty/ralph-isberg" target="_blank">Ralph Isberg</a>, a professor at the Tufts University School of Medicine. Joan Mecsas and Bree Aldridge, both from Tufts, and CITADel leaders <a href="/node/7600">Deb Hung</a>, ӳ����ý core institute member, and <a href="/node/446076">Laura Kiessling</a>, ӳ����ý institute member, also helped drive the work.</p> <h2>ESKAPE route</h2> <p>More than 1 million people die of antibiotic-resistant infections every year and doctors need new ways to treat these patients. None of the antibiotics discovered in the last 10 years kill bacteria through new mechanisms, and it is likely that bacteria will evolve to resist these newer treatments through existing resistance mechanisms. One potential approach to addressing this is to identify other molecules, called adjuvants, that can make bacteria more susceptible to existing antibiotics.</p> <p>“A novel adjuvant could really help us overcome resistance mechanisms and better address the antibiotic crisis,” said Megan Tse, who is a co-first author on the study along with Meilin Zhu. Both Tse and Zhu were graduate students in Blainey’s lab when the work began. </p> <p>Tse, Zhu, and their team wanted to use a combinatorial approach to treat so-called “ESKAPE” pathogens, a priority designation by the World Health Organization that includes <em>Klebsiella pneumoniae</em>, <em>Acinetobacter baumannii</em>, and <em>Pseudomonas aeruginosa</em>. In their new study, the scientists focused on these three Gram-negative bacteria. </p> <p>While it might be straightforward to test a single compound against a bacterial species, testing millions of combinations of molecules quickly becomes an “absurdly large” problem requiring specialized equipment, Tse says. </p> <p>So the team turned to a technology called <a href="https://www.pnas.org/doi/full/10.1073/pnas.1802233115" target="_blank">DropArray</a>, developed by Blainey’s lab in 2018. This technique uses microarrays of hundreds of thousands of wells to combine bacteria and compounds in thousands of nanoliter-sized droplets. Fluorescent barcodes mark the precise combination in each droplet. The researchers then use a microscope to track the growth of bacteria in each well, looking for wells where bacteria don’t grow at all due to an effective combination of bacterial-killing molecules. </p> <p>To identify molecules that might help target ESKAPE pathogens, Tse, Zhu, and their colleagues scaled up the approach to analyze a panel of six bacteria, 22 known antibiotics at different concentrations, and 30,000 chemical compounds — testing about 1.3 million combinations in just one month. The team looked for molecules that had effects in multiple species.</p> <p>One compound, a molecule called P2-56, stood out. It made multiple antibiotics more effective in <em>A. baumannii</em> and <em>K. pneumoniae</em> and at least one antibiotic more effective in all of the ESKAPE species. The team also developed a more potent version of the molecule called P2-56-3 that made the antibiotic rifampin even more effective.</p> <h2>Membrane disruption</h2> <p>In additional experiments, Tse working in collaboration with Isberg lab members found that P2-56-3 disrupts the outer membrane of <em>A. baumannii</em>’s cell envelope, potentially by disrupting lipooligosaccharide transport. This may increase the bacteria’s ability to take up antibiotics such as rifampin that don’t normally enter the cell.</p> <p>Additional work is needed to determine whether P2-56-3 and rifampin could be a viable combination therapy in people. But Blainey says their technology makes possible a previously inaccessible goal of large-scale combination screening. He hopes other groups will use his team’s dataset to interpret their own results and train new computational models to predict antibiotic activity.</p> <p>“We’ve shown that with this technology and throughput, combination screening is a doable thing,” Blainey said. “I hope this expands people’s imaginations of what can be done.”</p> <p><iframe allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen frameborder="0" height="315" src="https://www.youtube.com/embed/l8NkGTSt0Ks?si=sZ_WacO1CAXO0pq2" title="YouTube video player" width="560"></iframe></p> <p><em>A video about the original DropArray technique, a tool for identifying compounds that improve the efficacy of antibiotics against bacteria.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>This work was supported in part by the National Institutes of Health, the Merkin Institute for Transformative Technologies in Healthcare, the Koch Institute for Integrative Cancer Research at MIT, and the Defense Advanced Research Projects Agency.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Tse M W, Zhu M et al. <a href="https://www.pnas.org/doi/10.1073/pnas.2402017122" target="_blank">Massively parallel combination screen reveals small molecule sensitization of antibiotic-resistant Gram-negative <em>ESKAPE</em> pathogens</a>. PNAS. Online March 24, 2025. DOI: 10.1073/pnas.2402017122.</p> <p>  </p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/blainey-lab" hreflang="en">Blainey Lab</a></div> </div> </div> </div> </div> </div> Mon, 07 Nov 2022 16:05:51 +0000 tulrich@broadinstitute.org 1245906 at /news/crispr-based-diagnostic-chips-perform-thousands-tests-simultaneously-detect-viruses <span class="field field--name-title field--type-string field--label-hidden"><h1>Making antibiotics more potent against drug-resistant bacteria</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Allessandra DiCorato</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2025-05-28T09:00:00-04:00" class="datetime">May 28, 2025</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Making antibiotics more potent against drug-resistant bacteria</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Scientists find combinations of known antibiotics and other molecules that, together, have greater bacteria-killing power.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Allessandra DiCorato </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2025-05-28T09:00:00-04:00" title="Wednesday, May 28, 2025 - 09:00" class="datetime">May 28, 2025</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/p_aeruginosa_main.png?itok=kGsZgTvT 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/p_aeruginosa_main.png?itok=kGsZgTvT 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/p_aeruginosa_main.png?itok=-8trp1oA 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"/> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/p_aeruginosa_main.png?itok=PwinDE1N 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"/> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/p_aeruginosa_main.png?itok=XKyhkUVZ 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"/> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/p_aeruginosa_main.png?itok=gUqS-cB5 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"/> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/p_aeruginosa_main.png?itok=gUqS-cB5" alt="illustration showing pink bacteria on a blue background" title="illustration showing pink bacteria on a blue background" typeof="foaf:Image" /> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Medical Illustrator: Jennifer Oosthuizen </div> <div class="media-caption__description"> An illustration depicting Pseudomonas aeruginosa bacteria, which are multi-drug resistant. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous" /></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/599/feed&title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#facebook" /> </svg> </a> <a href="https://twitter.com/intent/tweet?text=+/taxonomy/term/599/feed" target="_blank" title="Share to X" aria-label="Share to X" class="social-sharing-buttons-button share-x" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#x" /> </svg> </a> <a href="mailto:?subject=&body=/taxonomy/term/599/feed" title="Share to Email" aria-label="Share to Email" class="social-sharing-buttons-button share-email" target="_blank" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-narrow paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Researchers have created a pipeline for discovering unique combinations of molecules that increase the effectiveness of antibiotics against drug-resistant bacteria. The team, led by scientists at the ӳ����ý and the Tufts University School of Medicine, used a microfluidic approach to screen more than 1 million combinations of antibiotics, small molecules, and bacteria. They identified a small molecule that boosts the power of the antibiotic rifampin in certain bacteria by weakening their defenses. The team also developed another molecule that was even more potent. </p> <p>The findings were recently published in <em><a href="https://www.pnas.org/doi/10.1073/pnas.2402017122" target="_blank">PNAS</a></em> and come from the Center for Innovation to Transform Antibiotic Discovery (<a href="https://reporter.nih.gov/search/fNL_12Nusky7tnR9NlUwQA/project-details/10670154" target="_blank">CITADel</a>) at the ӳ����ý and MIT. CITADel aims to accelerate discovery of antibiotics against Gram-negative bacteria that can be particularly difficult to treat and often develop resistance.</p> <p><a href="/node/7575">Paul Blainey</a>, core member of the ӳ����ý and a professor of biological engineering at MIT, was a co-senior author on the study along with <a href="https://medicine.tufts.edu/people/faculty/ralph-isberg" target="_blank">Ralph Isberg</a>, a professor at the Tufts University School of Medicine. Joan Mecsas and Bree Aldridge, both from Tufts, and CITADel leaders <a href="/node/7600">Deb Hung</a>, ӳ����ý core institute member, and <a href="/node/446076">Laura Kiessling</a>, ӳ����ý institute member, also helped drive the work.</p> <h2>ESKAPE route</h2> <p>More than 1 million people die of antibiotic-resistant infections every year and doctors need new ways to treat these patients. None of the antibiotics discovered in the last 10 years kill bacteria through new mechanisms, and it is likely that bacteria will evolve to resist these newer treatments through existing resistance mechanisms. One potential approach to addressing this is to identify other molecules, called adjuvants, that can make bacteria more susceptible to existing antibiotics.</p> <p>“A novel adjuvant could really help us overcome resistance mechanisms and better address the antibiotic crisis,” said Megan Tse, who is a co-first author on the study along with Meilin Zhu. Both Tse and Zhu were graduate students in Blainey’s lab when the work began. </p> <p>Tse, Zhu, and their team wanted to use a combinatorial approach to treat so-called “ESKAPE” pathogens, a priority designation by the World Health Organization that includes <em>Klebsiella pneumoniae</em>, <em>Acinetobacter baumannii</em>, and <em>Pseudomonas aeruginosa</em>. In their new study, the scientists focused on these three Gram-negative bacteria. </p> <p>While it might be straightforward to test a single compound against a bacterial species, testing millions of combinations of molecules quickly becomes an “absurdly large” problem requiring specialized equipment, Tse says. </p> <p>So the team turned to a technology called <a href="https://www.pnas.org/doi/full/10.1073/pnas.1802233115" target="_blank">DropArray</a>, developed by Blainey’s lab in 2018. This technique uses microarrays of hundreds of thousands of wells to combine bacteria and compounds in thousands of nanoliter-sized droplets. Fluorescent barcodes mark the precise combination in each droplet. The researchers then use a microscope to track the growth of bacteria in each well, looking for wells where bacteria don’t grow at all due to an effective combination of bacterial-killing molecules. </p> <p>To identify molecules that might help target ESKAPE pathogens, Tse, Zhu, and their colleagues scaled up the approach to analyze a panel of six bacteria, 22 known antibiotics at different concentrations, and 30,000 chemical compounds — testing about 1.3 million combinations in just one month. The team looked for molecules that had effects in multiple species.</p> <p>One compound, a molecule called P2-56, stood out. It made multiple antibiotics more effective in <em>A. baumannii</em> and <em>K. pneumoniae</em> and at least one antibiotic more effective in all of the ESKAPE species. The team also developed a more potent version of the molecule called P2-56-3 that made the antibiotic rifampin even more effective.</p> <h2>Membrane disruption</h2> <p>In additional experiments, Tse working in collaboration with Isberg lab members found that P2-56-3 disrupts the outer membrane of <em>A. baumannii</em>’s cell envelope, potentially by disrupting lipooligosaccharide transport. This may increase the bacteria’s ability to take up antibiotics such as rifampin that don’t normally enter the cell.</p> <p>Additional work is needed to determine whether P2-56-3 and rifampin could be a viable combination therapy in people. But Blainey says their technology makes possible a previously inaccessible goal of large-scale combination screening. He hopes other groups will use his team’s dataset to interpret their own results and train new computational models to predict antibiotic activity.</p> <p>“We’ve shown that with this technology and throughput, combination screening is a doable thing,” Blainey said. “I hope this expands people’s imaginations of what can be done.”</p> <p><iframe allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen frameborder="0" height="315" src="https://www.youtube.com/embed/l8NkGTSt0Ks?si=sZ_WacO1CAXO0pq2" title="YouTube video player" width="560"></iframe></p> <p><em>A video about the original DropArray technique, a tool for identifying compounds that improve the efficacy of antibiotics against bacteria.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>This work was supported in part by the National Institutes of Health, the Merkin Institute for Transformative Technologies in Healthcare, the Koch Institute for Integrative Cancer Research at MIT, and the Defense Advanced Research Projects Agency.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Tse M W, Zhu M et al. <a href="https://www.pnas.org/doi/10.1073/pnas.2402017122" target="_blank">Massively parallel combination screen reveals small molecule sensitization of antibiotic-resistant Gram-negative <em>ESKAPE</em> pathogens</a>. PNAS. Online March 24, 2025. DOI: 10.1073/pnas.2402017122.</p> <p>  </p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/blainey-lab" hreflang="en">Blainey Lab</a></div> </div> </div> </div> </div> </div> Wed, 29 Apr 2020 09:22:24 +0000 kzusi@broadinstitute.org 628401 at /news/new-microfluidics-platform-separates-cell-types-rna-profiling <span class="field field--name-title field--type-string field--label-hidden"><h1>Making antibiotics more potent against drug-resistant bacteria</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Allessandra DiCorato</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2025-05-28T09:00:00-04:00" class="datetime">May 28, 2025</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Making antibiotics more potent against drug-resistant bacteria</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Scientists find combinations of known antibiotics and other molecules that, together, have greater bacteria-killing power.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Allessandra DiCorato </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2025-05-28T09:00:00-04:00" title="Wednesday, May 28, 2025 - 09:00" class="datetime">May 28, 2025</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/p_aeruginosa_main.png?itok=kGsZgTvT 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/p_aeruginosa_main.png?itok=kGsZgTvT 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/p_aeruginosa_main.png?itok=-8trp1oA 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"/> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/p_aeruginosa_main.png?itok=PwinDE1N 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"/> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/p_aeruginosa_main.png?itok=XKyhkUVZ 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"/> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/p_aeruginosa_main.png?itok=gUqS-cB5 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"/> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/p_aeruginosa_main.png?itok=gUqS-cB5" alt="illustration showing pink bacteria on a blue background" title="illustration showing pink bacteria on a blue background" typeof="foaf:Image" /> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Medical Illustrator: Jennifer Oosthuizen </div> <div class="media-caption__description"> An illustration depicting Pseudomonas aeruginosa bacteria, which are multi-drug resistant. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous" /></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/599/feed&title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#facebook" /> </svg> </a> <a href="https://twitter.com/intent/tweet?text=+/taxonomy/term/599/feed" target="_blank" title="Share to X" aria-label="Share to X" class="social-sharing-buttons-button share-x" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#x" /> </svg> </a> <a href="mailto:?subject=&body=/taxonomy/term/599/feed" title="Share to Email" aria-label="Share to Email" class="social-sharing-buttons-button share-email" target="_blank" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-narrow paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Researchers have created a pipeline for discovering unique combinations of molecules that increase the effectiveness of antibiotics against drug-resistant bacteria. The team, led by scientists at the ӳ����ý and the Tufts University School of Medicine, used a microfluidic approach to screen more than 1 million combinations of antibiotics, small molecules, and bacteria. They identified a small molecule that boosts the power of the antibiotic rifampin in certain bacteria by weakening their defenses. The team also developed another molecule that was even more potent. </p> <p>The findings were recently published in <em><a href="https://www.pnas.org/doi/10.1073/pnas.2402017122" target="_blank">PNAS</a></em> and come from the Center for Innovation to Transform Antibiotic Discovery (<a href="https://reporter.nih.gov/search/fNL_12Nusky7tnR9NlUwQA/project-details/10670154" target="_blank">CITADel</a>) at the ӳ����ý and MIT. CITADel aims to accelerate discovery of antibiotics against Gram-negative bacteria that can be particularly difficult to treat and often develop resistance.</p> <p><a href="/node/7575">Paul Blainey</a>, core member of the ӳ����ý and a professor of biological engineering at MIT, was a co-senior author on the study along with <a href="https://medicine.tufts.edu/people/faculty/ralph-isberg" target="_blank">Ralph Isberg</a>, a professor at the Tufts University School of Medicine. Joan Mecsas and Bree Aldridge, both from Tufts, and CITADel leaders <a href="/node/7600">Deb Hung</a>, ӳ����ý core institute member, and <a href="/node/446076">Laura Kiessling</a>, ӳ����ý institute member, also helped drive the work.</p> <h2>ESKAPE route</h2> <p>More than 1 million people die of antibiotic-resistant infections every year and doctors need new ways to treat these patients. None of the antibiotics discovered in the last 10 years kill bacteria through new mechanisms, and it is likely that bacteria will evolve to resist these newer treatments through existing resistance mechanisms. One potential approach to addressing this is to identify other molecules, called adjuvants, that can make bacteria more susceptible to existing antibiotics.</p> <p>“A novel adjuvant could really help us overcome resistance mechanisms and better address the antibiotic crisis,” said Megan Tse, who is a co-first author on the study along with Meilin Zhu. Both Tse and Zhu were graduate students in Blainey’s lab when the work began. </p> <p>Tse, Zhu, and their team wanted to use a combinatorial approach to treat so-called “ESKAPE” pathogens, a priority designation by the World Health Organization that includes <em>Klebsiella pneumoniae</em>, <em>Acinetobacter baumannii</em>, and <em>Pseudomonas aeruginosa</em>. In their new study, the scientists focused on these three Gram-negative bacteria. </p> <p>While it might be straightforward to test a single compound against a bacterial species, testing millions of combinations of molecules quickly becomes an “absurdly large” problem requiring specialized equipment, Tse says. </p> <p>So the team turned to a technology called <a href="https://www.pnas.org/doi/full/10.1073/pnas.1802233115" target="_blank">DropArray</a>, developed by Blainey’s lab in 2018. This technique uses microarrays of hundreds of thousands of wells to combine bacteria and compounds in thousands of nanoliter-sized droplets. Fluorescent barcodes mark the precise combination in each droplet. The researchers then use a microscope to track the growth of bacteria in each well, looking for wells where bacteria don’t grow at all due to an effective combination of bacterial-killing molecules. </p> <p>To identify molecules that might help target ESKAPE pathogens, Tse, Zhu, and their colleagues scaled up the approach to analyze a panel of six bacteria, 22 known antibiotics at different concentrations, and 30,000 chemical compounds — testing about 1.3 million combinations in just one month. The team looked for molecules that had effects in multiple species.</p> <p>One compound, a molecule called P2-56, stood out. It made multiple antibiotics more effective in <em>A. baumannii</em> and <em>K. pneumoniae</em> and at least one antibiotic more effective in all of the ESKAPE species. The team also developed a more potent version of the molecule called P2-56-3 that made the antibiotic rifampin even more effective.</p> <h2>Membrane disruption</h2> <p>In additional experiments, Tse working in collaboration with Isberg lab members found that P2-56-3 disrupts the outer membrane of <em>A. baumannii</em>’s cell envelope, potentially by disrupting lipooligosaccharide transport. This may increase the bacteria’s ability to take up antibiotics such as rifampin that don’t normally enter the cell.</p> <p>Additional work is needed to determine whether P2-56-3 and rifampin could be a viable combination therapy in people. But Blainey says their technology makes possible a previously inaccessible goal of large-scale combination screening. He hopes other groups will use his team’s dataset to interpret their own results and train new computational models to predict antibiotic activity.</p> <p>“We’ve shown that with this technology and throughput, combination screening is a doable thing,” Blainey said. “I hope this expands people’s imaginations of what can be done.”</p> <p><iframe allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen frameborder="0" height="315" src="https://www.youtube.com/embed/l8NkGTSt0Ks?si=sZ_WacO1CAXO0pq2" title="YouTube video player" width="560"></iframe></p> <p><em>A video about the original DropArray technique, a tool for identifying compounds that improve the efficacy of antibiotics against bacteria.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>This work was supported in part by the National Institutes of Health, the Merkin Institute for Transformative Technologies in Healthcare, the Koch Institute for Integrative Cancer Research at MIT, and the Defense Advanced Research Projects Agency.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Tse M W, Zhu M et al. <a href="https://www.pnas.org/doi/10.1073/pnas.2402017122" target="_blank">Massively parallel combination screen reveals small molecule sensitization of antibiotic-resistant Gram-negative <em>ESKAPE</em> pathogens</a>. PNAS. Online March 24, 2025. DOI: 10.1073/pnas.2402017122.</p> <p>  </p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/blainey-lab" hreflang="en">Blainey Lab</a></div> </div> </div> </div> </div> </div> Fri, 01 Feb 2019 15:56:24 +0000 kzusi@broadinstitute.org 451761 at /news/research-roundup-february-1-2019 <span class="field field--name-title field--type-string field--label-hidden"><h1>Making antibiotics more potent against drug-resistant bacteria</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Allessandra DiCorato</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2025-05-28T09:00:00-04:00" class="datetime">May 28, 2025</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Making antibiotics more potent against drug-resistant bacteria</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Scientists find combinations of known antibiotics and other molecules that, together, have greater bacteria-killing power.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Allessandra DiCorato </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2025-05-28T09:00:00-04:00" title="Wednesday, May 28, 2025 - 09:00" class="datetime">May 28, 2025</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/p_aeruginosa_main.png?itok=kGsZgTvT 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/p_aeruginosa_main.png?itok=kGsZgTvT 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/p_aeruginosa_main.png?itok=-8trp1oA 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"/> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/p_aeruginosa_main.png?itok=PwinDE1N 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"/> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/p_aeruginosa_main.png?itok=XKyhkUVZ 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"/> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/p_aeruginosa_main.png?itok=gUqS-cB5 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"/> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/p_aeruginosa_main.png?itok=gUqS-cB5" alt="illustration showing pink bacteria on a blue background" title="illustration showing pink bacteria on a blue background" typeof="foaf:Image" /> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Medical Illustrator: Jennifer Oosthuizen </div> <div class="media-caption__description"> An illustration depicting Pseudomonas aeruginosa bacteria, which are multi-drug resistant. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous" /></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/599/feed&title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#facebook" /> </svg> </a> <a href="https://twitter.com/intent/tweet?text=+/taxonomy/term/599/feed" target="_blank" title="Share to X" aria-label="Share to X" class="social-sharing-buttons-button share-x" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#x" /> </svg> </a> <a href="mailto:?subject=&body=/taxonomy/term/599/feed" title="Share to Email" aria-label="Share to Email" class="social-sharing-buttons-button share-email" target="_blank" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-narrow paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Researchers have created a pipeline for discovering unique combinations of molecules that increase the effectiveness of antibiotics against drug-resistant bacteria. The team, led by scientists at the ӳ����ý and the Tufts University School of Medicine, used a microfluidic approach to screen more than 1 million combinations of antibiotics, small molecules, and bacteria. They identified a small molecule that boosts the power of the antibiotic rifampin in certain bacteria by weakening their defenses. The team also developed another molecule that was even more potent. </p> <p>The findings were recently published in <em><a href="https://www.pnas.org/doi/10.1073/pnas.2402017122" target="_blank">PNAS</a></em> and come from the Center for Innovation to Transform Antibiotic Discovery (<a href="https://reporter.nih.gov/search/fNL_12Nusky7tnR9NlUwQA/project-details/10670154" target="_blank">CITADel</a>) at the ӳ����ý and MIT. CITADel aims to accelerate discovery of antibiotics against Gram-negative bacteria that can be particularly difficult to treat and often develop resistance.</p> <p><a href="/node/7575">Paul Blainey</a>, core member of the ӳ����ý and a professor of biological engineering at MIT, was a co-senior author on the study along with <a href="https://medicine.tufts.edu/people/faculty/ralph-isberg" target="_blank">Ralph Isberg</a>, a professor at the Tufts University School of Medicine. Joan Mecsas and Bree Aldridge, both from Tufts, and CITADel leaders <a href="/node/7600">Deb Hung</a>, ӳ����ý core institute member, and <a href="/node/446076">Laura Kiessling</a>, ӳ����ý institute member, also helped drive the work.</p> <h2>ESKAPE route</h2> <p>More than 1 million people die of antibiotic-resistant infections every year and doctors need new ways to treat these patients. None of the antibiotics discovered in the last 10 years kill bacteria through new mechanisms, and it is likely that bacteria will evolve to resist these newer treatments through existing resistance mechanisms. One potential approach to addressing this is to identify other molecules, called adjuvants, that can make bacteria more susceptible to existing antibiotics.</p> <p>“A novel adjuvant could really help us overcome resistance mechanisms and better address the antibiotic crisis,” said Megan Tse, who is a co-first author on the study along with Meilin Zhu. Both Tse and Zhu were graduate students in Blainey’s lab when the work began. </p> <p>Tse, Zhu, and their team wanted to use a combinatorial approach to treat so-called “ESKAPE” pathogens, a priority designation by the World Health Organization that includes <em>Klebsiella pneumoniae</em>, <em>Acinetobacter baumannii</em>, and <em>Pseudomonas aeruginosa</em>. In their new study, the scientists focused on these three Gram-negative bacteria. </p> <p>While it might be straightforward to test a single compound against a bacterial species, testing millions of combinations of molecules quickly becomes an “absurdly large” problem requiring specialized equipment, Tse says. </p> <p>So the team turned to a technology called <a href="https://www.pnas.org/doi/full/10.1073/pnas.1802233115" target="_blank">DropArray</a>, developed by Blainey’s lab in 2018. This technique uses microarrays of hundreds of thousands of wells to combine bacteria and compounds in thousands of nanoliter-sized droplets. Fluorescent barcodes mark the precise combination in each droplet. The researchers then use a microscope to track the growth of bacteria in each well, looking for wells where bacteria don’t grow at all due to an effective combination of bacterial-killing molecules. </p> <p>To identify molecules that might help target ESKAPE pathogens, Tse, Zhu, and their colleagues scaled up the approach to analyze a panel of six bacteria, 22 known antibiotics at different concentrations, and 30,000 chemical compounds — testing about 1.3 million combinations in just one month. The team looked for molecules that had effects in multiple species.</p> <p>One compound, a molecule called P2-56, stood out. It made multiple antibiotics more effective in <em>A. baumannii</em> and <em>K. pneumoniae</em> and at least one antibiotic more effective in all of the ESKAPE species. The team also developed a more potent version of the molecule called P2-56-3 that made the antibiotic rifampin even more effective.</p> <h2>Membrane disruption</h2> <p>In additional experiments, Tse working in collaboration with Isberg lab members found that P2-56-3 disrupts the outer membrane of <em>A. baumannii</em>’s cell envelope, potentially by disrupting lipooligosaccharide transport. This may increase the bacteria’s ability to take up antibiotics such as rifampin that don’t normally enter the cell.</p> <p>Additional work is needed to determine whether P2-56-3 and rifampin could be a viable combination therapy in people. But Blainey says their technology makes possible a previously inaccessible goal of large-scale combination screening. He hopes other groups will use his team’s dataset to interpret their own results and train new computational models to predict antibiotic activity.</p> <p>“We’ve shown that with this technology and throughput, combination screening is a doable thing,” Blainey said. “I hope this expands people’s imaginations of what can be done.”</p> <p><iframe allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen frameborder="0" height="315" src="https://www.youtube.com/embed/l8NkGTSt0Ks?si=sZ_WacO1CAXO0pq2" title="YouTube video player" width="560"></iframe></p> <p><em>A video about the original DropArray technique, a tool for identifying compounds that improve the efficacy of antibiotics against bacteria.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>This work was supported in part by the National Institutes of Health, the Merkin Institute for Transformative Technologies in Healthcare, the Koch Institute for Integrative Cancer Research at MIT, and the Defense Advanced Research Projects Agency.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Tse M W, Zhu M et al. <a href="https://www.pnas.org/doi/10.1073/pnas.2402017122" target="_blank">Massively parallel combination screen reveals small molecule sensitization of antibiotic-resistant Gram-negative <em>ESKAPE</em> pathogens</a>. PNAS. Online March 24, 2025. DOI: 10.1073/pnas.2402017122.</p> <p>  </p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/blainey-lab" hreflang="en">Blainey Lab</a></div> </div> </div> </div> </div> </div> Fri, 01 Feb 2019 15:49:02 +0000 tulrich@broadinstitute.org 447516 at /scientific-community/software/prism <span class="field field--name-title field--type-string field--label-hidden"><h1>Making antibiotics more potent against drug-resistant bacteria</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Allessandra DiCorato</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2025-05-28T09:00:00-04:00" class="datetime">May 28, 2025</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Making antibiotics more potent against drug-resistant bacteria</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Scientists find combinations of known antibiotics and other molecules that, together, have greater bacteria-killing power.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Allessandra DiCorato </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2025-05-28T09:00:00-04:00" title="Wednesday, May 28, 2025 - 09:00" class="datetime">May 28, 2025</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/p_aeruginosa_main.png?itok=kGsZgTvT 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/p_aeruginosa_main.png?itok=kGsZgTvT 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/p_aeruginosa_main.png?itok=-8trp1oA 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"/> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/p_aeruginosa_main.png?itok=PwinDE1N 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"/> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/p_aeruginosa_main.png?itok=XKyhkUVZ 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"/> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/p_aeruginosa_main.png?itok=gUqS-cB5 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"/> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/p_aeruginosa_main.png?itok=gUqS-cB5" alt="illustration showing pink bacteria on a blue background" title="illustration showing pink bacteria on a blue background" typeof="foaf:Image" /> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Medical Illustrator: Jennifer Oosthuizen </div> <div class="media-caption__description"> An illustration depicting Pseudomonas aeruginosa bacteria, which are multi-drug resistant. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous" /></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/599/feed&title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#facebook" /> </svg> </a> <a href="https://twitter.com/intent/tweet?text=+/taxonomy/term/599/feed" target="_blank" title="Share to X" aria-label="Share to X" class="social-sharing-buttons-button share-x" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#x" /> </svg> </a> <a href="mailto:?subject=&body=/taxonomy/term/599/feed" title="Share to Email" aria-label="Share to Email" class="social-sharing-buttons-button share-email" target="_blank" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#email" /> </svg> </a> </div> </div> <div class="block block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-narrow paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Researchers have created a pipeline for discovering unique combinations of molecules that increase the effectiveness of antibiotics against drug-resistant bacteria. The team, led by scientists at the ӳ����ý and the Tufts University School of Medicine, used a microfluidic approach to screen more than 1 million combinations of antibiotics, small molecules, and bacteria. They identified a small molecule that boosts the power of the antibiotic rifampin in certain bacteria by weakening their defenses. The team also developed another molecule that was even more potent. </p> <p>The findings were recently published in <em><a href="https://www.pnas.org/doi/10.1073/pnas.2402017122" target="_blank">PNAS</a></em> and come from the Center for Innovation to Transform Antibiotic Discovery (<a href="https://reporter.nih.gov/search/fNL_12Nusky7tnR9NlUwQA/project-details/10670154" target="_blank">CITADel</a>) at the ӳ����ý and MIT. CITADel aims to accelerate discovery of antibiotics against Gram-negative bacteria that can be particularly difficult to treat and often develop resistance.</p> <p><a href="/node/7575">Paul Blainey</a>, core member of the ӳ����ý and a professor of biological engineering at MIT, was a co-senior author on the study along with <a href="https://medicine.tufts.edu/people/faculty/ralph-isberg" target="_blank">Ralph Isberg</a>, a professor at the Tufts University School of Medicine. Joan Mecsas and Bree Aldridge, both from Tufts, and CITADel leaders <a href="/node/7600">Deb Hung</a>, ӳ����ý core institute member, and <a href="/node/446076">Laura Kiessling</a>, ӳ����ý institute member, also helped drive the work.</p> <h2>ESKAPE route</h2> <p>More than 1 million people die of antibiotic-resistant infections every year and doctors need new ways to treat these patients. None of the antibiotics discovered in the last 10 years kill bacteria through new mechanisms, and it is likely that bacteria will evolve to resist these newer treatments through existing resistance mechanisms. One potential approach to addressing this is to identify other molecules, called adjuvants, that can make bacteria more susceptible to existing antibiotics.</p> <p>“A novel adjuvant could really help us overcome resistance mechanisms and better address the antibiotic crisis,” said Megan Tse, who is a co-first author on the study along with Meilin Zhu. Both Tse and Zhu were graduate students in Blainey’s lab when the work began. </p> <p>Tse, Zhu, and their team wanted to use a combinatorial approach to treat so-called “ESKAPE” pathogens, a priority designation by the World Health Organization that includes <em>Klebsiella pneumoniae</em>, <em>Acinetobacter baumannii</em>, and <em>Pseudomonas aeruginosa</em>. In their new study, the scientists focused on these three Gram-negative bacteria. </p> <p>While it might be straightforward to test a single compound against a bacterial species, testing millions of combinations of molecules quickly becomes an “absurdly large” problem requiring specialized equipment, Tse says. </p> <p>So the team turned to a technology called <a href="https://www.pnas.org/doi/full/10.1073/pnas.1802233115" target="_blank">DropArray</a>, developed by Blainey’s lab in 2018. This technique uses microarrays of hundreds of thousands of wells to combine bacteria and compounds in thousands of nanoliter-sized droplets. Fluorescent barcodes mark the precise combination in each droplet. The researchers then use a microscope to track the growth of bacteria in each well, looking for wells where bacteria don’t grow at all due to an effective combination of bacterial-killing molecules. </p> <p>To identify molecules that might help target ESKAPE pathogens, Tse, Zhu, and their colleagues scaled up the approach to analyze a panel of six bacteria, 22 known antibiotics at different concentrations, and 30,000 chemical compounds — testing about 1.3 million combinations in just one month. The team looked for molecules that had effects in multiple species.</p> <p>One compound, a molecule called P2-56, stood out. It made multiple antibiotics more effective in <em>A. baumannii</em> and <em>K. pneumoniae</em> and at least one antibiotic more effective in all of the ESKAPE species. The team also developed a more potent version of the molecule called P2-56-3 that made the antibiotic rifampin even more effective.</p> <h2>Membrane disruption</h2> <p>In additional experiments, Tse working in collaboration with Isberg lab members found that P2-56-3 disrupts the outer membrane of <em>A. baumannii</em>’s cell envelope, potentially by disrupting lipooligosaccharide transport. This may increase the bacteria’s ability to take up antibiotics such as rifampin that don’t normally enter the cell.</p> <p>Additional work is needed to determine whether P2-56-3 and rifampin could be a viable combination therapy in people. But Blainey says their technology makes possible a previously inaccessible goal of large-scale combination screening. He hopes other groups will use his team’s dataset to interpret their own results and train new computational models to predict antibiotic activity.</p> <p>“We’ve shown that with this technology and throughput, combination screening is a doable thing,” Blainey said. “I hope this expands people’s imaginations of what can be done.”</p> <p><iframe allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen frameborder="0" height="315" src="https://www.youtube.com/embed/l8NkGTSt0Ks?si=sZ_WacO1CAXO0pq2" title="YouTube video player" width="560"></iframe></p> <p><em>A video about the original DropArray technique, a tool for identifying compounds that improve the efficacy of antibiotics against bacteria.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>This work was supported in part by the National Institutes of Health, the Merkin Institute for Transformative Technologies in Healthcare, the Koch Institute for Integrative Cancer Research at MIT, and the Defense Advanced Research Projects Agency.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Tse M W, Zhu M et al. <a href="https://www.pnas.org/doi/10.1073/pnas.2402017122" target="_blank">Massively parallel combination screen reveals small molecule sensitization of antibiotic-resistant Gram-negative <em>ESKAPE</em> pathogens</a>. PNAS. Online March 24, 2025. DOI: 10.1073/pnas.2402017122.</p> <p>  </p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/blainey-lab" hreflang="en">Blainey Lab</a></div> </div> </div> </div> </div> </div> Tue, 25 May 2010 14:36:05 +0000 admin 1465 at