College News


Researcher honing in on life-giving drug for those suffering from TB

russellIn a paradigm-shifting collaborative relationship between Cornell University College of Veterinary Medicine and Vertex Pharmaceuticals, of Cambridge, Mass., Dr. David Russell is expanding the field of options for novel tuberculosis (TB) drug discovery. His long-term goal is to help the many millions around the world who suffer from tuberculosis, the disease caused by Mycobacterium tuberculosis, by finding new compounds that can reduce the treatment time and also be effective against drug-resistant TB. With initial screens of approximately 210,000 compounds (from the pharmaceutical company’s compound library) already finished, he says the collaboration has clearly provided access to new compounds with the potential to stop tuberculosis activity.

Historically, most pharmaceutical companies dedicate their compound libraries to in-house testing that focuses on target-based screening: working with molecules that have known applications for particular diseases. In target-based drug screening, tests are usually developed for a specific enzyme, receptor or other specific protein target in a pathway known to be necessary for pathogen survival. Libraries of compounds are analyzed, with the goal of finding inhibitors of an already known and characterized target.

Russell, professor of molecular microbiology, is looking for new drugs that have the capacity to shorten the treatment regimen by identifying compounds that can kill the TB bacterium quickly and also prevent it from persisting in the host by hiding out in a virtually dormant state.

“For decades, we have been remodeling known compounds,” said Russell. “We have pretty much exhausted all of the logical solutions in the world of drug remodeling for tuberculosis. We need to find new options, which can only be done if we introduce new compounds and new assays into the equation. Vertex has been incredibly generous, extremely flexible, and has shown tremendous foresight, and we hope that their compound collection may yield a novel new approach to the treatment of TB. They’ve thrown open the doors both for scientific discovery as well as the opportunity to eradicate a terrible disease.”

To accomplish this goal, he is currently working with one of his research associates, Dr. Brian VanderVen, using cell-based assays and scoring the level of bacterial fitness in response to compounds in Vertex’s library. Although less commonly employed than target-based screening, cell-based screening has an increasingly important role in research and drug discovery, because it interrogates the pathogen in its true host environment. Cell-based screening offers several advantages: A compound’s usefulness is often best predicted by measuring the biological behavior inside living cells, where the molecular interactions can be evaluated within the context of the cellular environment. In addition, the potential toxicity and side effects are also more readily detected. Cell-based screening therefore offers an avenue to the discovery of truly novel drugs and targets. Although only about two-thirds of the way through Vertex’s library of molecules, to date, Russell and his team have identified approximately 500 compounds that will be re-evaluated with secondary reporter screens.

“We have identified an exciting list of compounds that possess a kill rate of 70 percent or better than most front-line drugs in use today for TB,” said Russell. “In addition, the screen generates statistically-robust data that are well above the accepted industrial standard for drug screens, despite the added difficulty we face due to the wide range of variables encountered when using live cell screens. If the identified compounds are capable of killing Mycobacterium tuberculosis with both primary and secondary screens then we will know that we have found an excellent lead compound with the potential for a new anti-TB drug, a drug that kills the TB bug inside its host. These compounds will be run through a third screen, to make sure that they're not also capable of killing the host.”

According to the World Health Organization, a person contracts the tuberculosis bacterium every second, and fully one-third of the world's population is currently infected with this pathogen. Although drugs for tuberculosis have only been available for about 50 years, some strains of the bacterium have already adapted, making them resistant to all major anti-tuberculosis drugs.

“Drug-resistant TB is caused by failure of treatment, either when patients do not take all their medicines regularly for the required period because they start to feel better, or because doctors and health workers prescribe the wrong treatment regimens, or do not have access to sufficient supplies of the drug,” said Russell.

The beauty of the cell-based screen is that it targets the entire unit of infection, where the bacterium persists inside its host cell, rather than focusing on the function of a single enzyme or protein target. Russell believes that this greatly increases the chance of success and the discovery of truly novel drugs against this infectious agent.

“Our work is only the beginning. The time between getting an initial hit and developing a drug is years,” said Russell. “Once the activity of a compound is validated, we will send it to synthetic chemists at Vertex who will aim to make a family of compounds to test for activity. Beyond that, Vertex will engage scientists to study the efficacy of the compound’s ability to be absorbed in the body and conduct additional research. We believe that our collaboration with Vertex may enable this complex series of scientific and logistical requirements to take place in a highly efficient and effective manner.”

Facilitated by JoAnne Williams, the director of Cornell’s Office of Sponsored Programs, the unique collaboration represents an unusual twist in the drug discovery paradigm. Pharmaceutical companies regard their compound library as their “lifeblood,” and it is rare for them to allow these collections to be screened outside their own facilities, according to Russell. In the collaboration, Vertex will control the future application of discoveries in tuberculosis, with a vision of developing therapies aimed at benefiting people with TB around the globe. The rights to apply these discoveries more broadly, outside the field of TB, will be shared by Vertex and Cornell.

“Our collaboration with Cornell underscores Vertex’s commitment to innovative science aimed at the discovery of new treatment options for serious diseases,” said John Thomson, Vice President of Strategic Research and Development Networks for Vertex. “Dr. Russell and his team are at the cutting edge of innovation in the fight against TB, and we look forward to working with them as part of this unique collaboration.”

“This is a measure of trust that has never been established before,” said Russell. “And it is our hope that people suffering around the world will be the beneficiaries.”

For more information on Vertex Pharmaceuticals, visit www.vrtx.com/. For more information on Cornell’s College of Veterinary Medicine, visit www.vet.cornell.edu.

russellThe image shows Mycobacterium tuberculosis transformed to express mCherry (red) constitutively, and GFP (green) under regulation of a pH-sensitive promoter. The bacteria are in macrophages that have endocytosed fluorescent dextran to label their lysosomes (blue). The picture was taken by Robert Abramovitch.