Researchers at Weill Cornell Medicine have received a $17.4 million, five-year grant from the National Institute of Allergy and Infectious Diseases to discover new approaches to shorten tuberculosis (TB) treatment, potentially making it easier for patients to complete therapy. The researchers aim to shift TB drug development toward creating new drugs from the start to work in the combinations needed to cure TB.
Though a course of antibiotics, when completed, can cure the infectious disease that most commonly affects the lungs, TB is still among the top 10 causes of death worldwide. "The current regimen works, but the drugs are far from ideal and must be taken over four to six months," said co-principal investigator Dr. Kyu Rhee, professor of medicine in the Division of Infectious Diseases and professor of microbiology and immunology at Weill Cornell. "They have serious side effects, so many patients stop taking them once they feel better but long before they are cured."
Other reasons patients stop treatment early include the ongoing financial burden and social stigma associated with TB, all of which ultimately contribute to relapses and the emergence of drug-resistant bacteria.
That type of relapse is much more difficult to cure than the initial infection. That's bad for the patient, but it is also a challenge from a global health perspective if the patient transmits drug-resistant bacteria to others."
Dr. Dirk Schnappinger, co-principal investigator, professor of microbiology and immunology, Weill Cornell Medicine
TB research has a rich history at Weill Cornell, where scientists and clinicians have helped develop therapies for more than 50 years. Over time, the treatment duration has decreased from one-and-a-half years to several months, but that is still too long for many patients to bear.
This grant adds the next chapter to the Weill Cornell story, funding four interrelated projects to understand how some tuberculosis bacteria resist treatment and identify survival mechanisms that can be targeted to eliminate bacteria more quickly.
"We're really generating the knowledge base required to develop shorter, simpler and safer cures for TB," said Dr. Rhee, who is also a physician at New York-Presbyterian/Weill Cornell Medical Center. "We know a lot about how antibiotics kill bacteria in a test tube but much less about how they cure infections in people and what determines how fast they work."
Dr. Schnappinger and Dr. Rhee, as well as Dr. Carl Nathan, professor of medicine and microbiology and immunology at Weill Cornell, will lead three of the projects.
"Using a gene silencing system that we have tailored for TB bacteria, my lab will study how the inactivation of various bacterial genes could kill them—not just stop them from growing," Dr. Schnappinger said.
Dr. Rhee's team will focus on understanding how two commonly used antibiotics, rifampin and pyrazinamide, help shorten treatment. They will investigate whether the underlying mechanisms can be exploited to discover new ways of further decreasing treatment time.
Dr. Jeremy Rock, associate professor at Rockefeller University, will lead a team that will build an atlas of genetic interactions in TB bacteria. This work aims to uncover combinations of targets that could weaken the bacteria and make them more vulnerable to therapies.
"One problem with treating TB is that the conditions in infected sites within people differ markedly from conditions in laboratories where TB drugs are developed," Dr. Nathan said. "Under host-relevant conditions, the bacteria are often tolerant to the drugs." His group will use a genome-wide approach developed by Dr. Rock to identify genes that the bacteria depend on to survive under host-relevant conditions. The proteins encoded by those genes could be targets for new drugs that overcome the bacteria's tolerance to existing drugs and thereby speed cure.
A key part of the effort will use newly developed single-cell technologies and machine learning methods developed by investigators at Weill Cornell and Tufts University to examine how individual bacteria respond to drugs and how their genes change. This could reveal small populations of bacteria that may contribute to longer treatment.
"Shortening TB treatment is a complex, high-level problem that can't be accomplished with just one strategy and one area of expertise," Dr. Schnappinger said. "Each team brings a different background in genomics, metabolomics, bioinformatics or clinical methods to address this challenging issue from multiple angles."
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