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<h2 class="element-invisible">You are here</h2><div class="breadcrumb"><a href="/">Home</a> » <a href="/news-events">News & Events</a> » <a href="/news-events/nih-research-matters">NIH Research Matters</a></div> <div class="l-region l-region--section-header">
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<p class="publishdate"><span property="dc:date" datatype="xsd:dateTime" content="2016-06-14T00:00:00-04:00" class="date-display-single">June 14, 2016</span></p><div class='syndicate'><h1>Predicting effective drug combinations for TB</h1><div class="callout callout-with-border"><h3>At a Glance</h3>
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<ul>
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<li>Researchers analyzed gene regulatory networks to explain the effectiveness of an experimental drug combination against drug-resistant tuberculosis bacteria.</li>
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<li>The approach could help speed the development of combination drug regimens against tuberculosis.</li>
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<picture title="Illustration of Mycobacterium tuberculosis">
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<!--[if IE 9]><video style="display: none;"><![endif]-->
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-large/public/news-events/research-matters/2016/20160614-tb.jpg?itok=UvJaFBG6&timestamp=1465906980 1x" media="screen and (min-width: 960px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium/public/news-events/research-matters/2016/20160614-tb.jpg?itok=fvf65sN0&timestamp=1465906980 1x" media="screen and (min-width: 800px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium-small/public/news-events/research-matters/2016/20160614-tb.jpg?itok=bTZisLyl&timestamp=1465906980 1x" media="screen and (min-width: 600px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-small/public/news-events/research-matters/2016/20160614-tb.jpg?itok=L4XZRV9-&timestamp=1465906980 1x" media="screen and (min-width: 480px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-tiny/public/news-events/research-matters/2016/20160614-tb.jpg?itok=oTW06flB&timestamp=1465906980 1x" media="screen and (min-width: 0)" />
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<!--[if IE 9]></video><![endif]-->
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<img src="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium/public/news-events/research-matters/2016/20160614-tb.jpg?itok=fvf65sN0&timestamp=1465906980" alt="Illustration of Mycobacterium tuberculosis" title="Illustration of Mycobacterium tuberculosis" />
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</picture><span class="caption">Understanding how Mtb dodges drug attacks will help researchers design strategies to overcome the bug's resistance.</span><span class="credit">Dr. Allison Kudla/Institute for Systems Biology</span></div>
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||
</div><p>Tuberculosis (TB) is a bacterial disease that has plagued people for millennia. In the 21<sup>st</sup> century, it’s still a formidable killer. According the World Health Organization, 1.5 million people died of TB in 2014; of those, about 480,000 had multidrug-resistant TB (MDR-TB), which is resistant to at least 2 of the most potent TB drugs available.</p>
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<p>The bacterium that causes TB, <em>Mycobacterium tuberculosis (Mtb)</em>, can withstand attacks by antibacterial drugs through a variety of mechanisms. Because of this resilience, TB drug therapy can stretch for months or even years, involve numerous drugs with harsh side effects, and still fail to cure the disease.</p>
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||
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||
<p>Researchers have been trying to understand how <em>Mtb</em> dodges drug attacks. They could use this knowledge to help predict which drugs or drug combinations are most likely to overcome the bug’s evasive maneuvers.</p>
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||
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||
<p>In previous work, scientists mapped the gene regulatory network in <em>Mtb</em>. In this study, researchers used this network model to investigate how <em>Mtb</em> can become tolerant to the relatively new anti-TB drug bedaquiline. The Seattle-based team was led by Dr. Nitin Baliga at the Institute for Systems Biology and Dr. David Sherman at the Center for Infectious Disease Research. The study was funded in part by NIH’s National Institute of Allergy and Infectious Diseases (NIAID). It appeared online in <em>Nature Microbiology</em> on June 6, 2016.</p>
|
||
|
||
<p>The team found that more than 1,100 genes were expressed differently in <em>Mtb</em> treated with bedaquiline compared to untreated bacteria. Using network analysis, the researchers pinpointed 2 key regulatory genes whose activation appeared to coordinate the changes that drive <em>Mtb</em> into a drug-tolerant state. When either of these genes was disrupted, the bacteria were once again susceptible to the drug in laboratory experiments.</p>
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||
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||
<p>Based on their system-wide understanding of how <em>Mtb</em> responds to bedaquiline, the researchers predicted which drug would be effective to use in combination with bedaquiline. The anti-TB drug pretomanid inhibits 1 of the 2 key gene networks activated by bedaquiline. In laboratory experiments, the team found that when pretomanid was used with bedaquiline the drugs acted synergistically to kill TB bacteria.</p>
|
||
|
||
<p>The drug combination is already being tested in several clinical trials, the researchers note. Their gene network analysis approach has helped illuminate the mechanism behind the combination’s effectiveness.</p>
|
||
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||
<p>“The incredibly large number of possible drug combinations taken together with the difficulty of growing <em>Mtb</em> in the laboratory make discovery of effective combination therapy extremely challenging," Baliga says. "We hope that our systems-based strategy will accelerate TB drug discovery by helping researchers prioritize combinations that are more likely to be effective.”</p>
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</div><h2 class="label-above">Related Links</h2><ul class="spaced print-urls"><li><a href="https://www.nih.gov/news-events/nih-research-matters/development-antibiotics-treat-tuberculosis" target="_top">Development of Antibiotics to Treat Tuberculosis</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/new-test-detects-tb-less-2-hours" target="_top">New Test Detects TB in Less than 2 Hours</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/drug-combination-defeats-deadliest-form-tuberculosis" target="_top">Drug Combination Defeats Deadliest Form of Tuberculosis</a></li><li><a href="http://www.niaid.nih.gov/topics/tuberculosis/Pages/Default.aspx" target="_top">Tuberculosis</a></li></ul><p class="footnote"><strong class="label-inline">References: </strong><a href="http://www.nature.com/articles/nmicrobiol201678">Network analysis identifies Rv0324 and Rv0880 as regulators of bedaquiline tolerance in Mycobacterium tuberculosis</a>. Peterson EJR, Shuyi M, Sherman DR, Baliga NS. <em>Nature Microbiology</em>. 2016 June 6. DOI: 10.1038/nmicrobiol.2016.78.</p><p class="footnote"><strong class="label-inline">Funding: </strong>NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and National Institute of General Medical Sciences (NIGMS).</p>
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<p><a href="https://www.nih.gov/news-events/nih-research-matters/brain-changes-observed-during-pregnancy">Brain changes observed during pregnancy</a></p>
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||
<p><a href="https://www.nih.gov/news-events/nih-research-matters/research-context-detecting-cancer">Research in Context: Detecting cancer</a></p>
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<p><a href="https://www.nih.gov/news-events/nih-research-matters/risk-future-burden-dementia-united-states">Risk and future burden of dementia in the United States </a></p>
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||
|
||
<p><a href="https://www.nih.gov/news-events/nih-research-matters/complete-wiring-map-adult-fruit-fly-brain">Complete wiring map of an adult fruit fly brain</a></p>
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<p><strong>Editor:</strong> Harrison Wein, Ph.D.</p>
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<p><strong><em>NIH Research Matters </em></strong>is a weekly update of NIH research highlights reviewed by NIH’s experts. It's published by the <a href="/institutes-nih/nih-office-director/office-communications-public-liaison">Office of Communications and Public Liaison</a> in the <a href="/institutes-nih/nih-office-director">NIH Office of the Director</a>.</p>
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