Speeding up drug discovery to fight tuberculosis

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  • Researchers at the Institute for Systems Biology and Center for Infectious Disease Research in Seattle have deciphered how the human pathogen Mycobacterium tuberculosis is able to tolerate the recently approved FDA drug bedaquiline.
  • The study demonstrated that silencing certain regulatory genes in the bacteria, or pairing with a second drug pretomanid, disrupts a tolerance gene network to improve efficacy of killing by bedaquiline.
  • This systems-approach to rational drug discovery represents significant advance in the fight against tuberculosis, which affects a third of the global population, surpassing HIV/AIDS in the number of deaths worldwide.

The rise in multi-drug resistant (MDR) and extremely drug resistant (XDR) strains of Mycobacterium tuberculosis (MTB) is becoming a major cause of global health concern for treating tuberculosis, which affects a third of the global population. In fact, the number of worldwide deaths caused by tuberculosis has surpassed HIV/AIDS, and there is greater sense of urgency than ever before to find effective drug cocktails to outsmart MTB.

In a landmark study to be published on June 6, 2016, in Nature Microbiology, researchers at Institute for Systems Biology and the Center for Infectious Disease Research in Seattle demonstrated a systems biology approach that has the potential to rationally predict combinations of drugs that will disrupt tolerance networks in MTB, making it even most susceptible to antibiotic therapy.

"The incredibly large number of possible drug combinations taken together with the difficulty of growing MTB in the laboratory make discovery of effective combination therapy extremely challenging. We hope that our systems-based strategy will accelerate TB drug discovery by helping researchers prioritize combinations that are more likely to be effective," said Dr. Nitin Baliga, of Institute for Systems Biology and the senior author on the paper.

The success of MTB is largely due to its ability to alter gene expression to counteract host defense and anti-tubercular drug treatment. An extended period of tolerance gives MTB a window of opportunity to mutate and evolve longer term resistance. Previously, researchers in the Baliga lab at ISB and in the Sherman lab at CIDR published a genome-wide regulatory network model that could predict how MTB senses and responds to changes in its environment, including anti-tubercular treatment.

In this study, they used the network model to understand how MTB tolerates killing by the drug bedaquiline, which in 2012 was the first drug in 40 years to be approved by the FDA. They used this network-enabled knowledge to find a second drug (pretomanid) to counteract tolerance against bedaquiline. They went on to demonstrate that making the tolerance network hyperactive abolished the effectiveness of the combination therapy, confirming the mechanism of combined action of bedaquiline and pretomanid. The success of this systems biology-based method to find drug combinations has the potential to revolutionize and rapidly accelerate efforts towards TB drug discovery.

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Funding was provided by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (U19 AI10676, U19 AI111276 and ISBpilot-10135) and the National Institute of General Medical Sciences of the National Institutes of Health (P50GM076547).

ABOUT INSTITUTE FOR SYSTEMS BIOLOGY: The Institute for Systems Biology is a nonprofit biomedical research organization based in Seattle, Washington. It was founded in 2000 by systems biologist Leroy Hood, immunologist Alan Aderem, and protein chemist Ruedi Aebersold. ISB was established on the belief that the conventional models for exploring and funding breakthrough science have not caught up with the real potential of what is possible today. ISB serves as the ultimate environment where scientific collaboration stretches across disciplines and across academic and industrial organizations, where our researchers have the intellectual freedom to challenge the status quo, and where grand visions for breakthroughs in human health inspire a collective drive to achieve the seemingly impossible. Our core values ensure that we always keep our focus on the big ideas that eventually will have the largest impact on human health. ISB is an affiliate of Providence Health & Services.

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Hsiao-Ching Chou
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