A novel compound developed by Cornell University researchers that has the potential to starve the bacteria that causes tuberculosis is entering human clinical trials.
The clinical trials will be funded by the Bill & Melinda Gates Foundation, which announced in February a strategic licensing agreement with biomedical research company Calibr to further develop the compound, CLB073, which has shown promise against Mycobacterium tuberculosis.
Under the agreement, Calibr has granted Bill & Melinda Gates Medical Research Institute an exclusive license to continue work on CLB073, which was developed by David Russell, PhD, the William Kaplan professor of infection biology in the College of Veterinary Medicine, and Brian VanderVen, PhD, associate professor in the Department of Microbiology and Immunology.
Russell said he expects the human clinical trial, which will test CLB073 for safety, to begin in the next few months and last about a year.
CLB073 works by eliminating the bacteria’s carbon source. The compound activates the enzyme adenylyl cyclase, which ultimately blocks Mycobacterium tuberculosis’ ability to metabolize cholesterol—essentially starving it.
“We don’t yet fully understand the mechanism of action, but the bottom line is it prevents the bacteria from eating cholesterol,” says VanderVen, who has been collaborating with Russell for the past 10 years, in a press release.
The key to the discovery, Russell says, was attacking the bacterium where it lives instead of the traditional model of putting the target bacterium in a solution of nutrient-rich broth for testing.
“Most drug discovery work is done in rich broth, and, in reality, the bacteria never sees rich broth,” he says in a press release. “So by putting the bacterium inside its host cell, you’re effectively constraining the bacteria’s ability to be flexible, which exposes additional drug targets. It was a theory that drove the drug screen, and it turned out to be correct.”
In preclinical mouse studies, CLB073 significantly enhanced the efficacy of Nix-TB drug regimen, the current standard of care for drug-resistant tuberculosis. In vivo testing has proven to be a game-changer, VanderVen says.
“We just asked a simple question: What kills the bacteria in the environment or the niche where it resides?” he says in a press release. “We screened the drugs in the context of the bacterium within its host cell, and that hasn’t been done on a large scale before.”
Russell says the mechanism behind CLB073 could be applicable to other diseases, as well.
“Brian has several other compounds that show much better activity in the host environment and minimal to no activity in broth,” he says in a press release. “So I don’t think it’s unique to this particular compound or mechanism; I think it’s a conceptual approach that has tremendous value.”
Cornell and Weill Cornell Medicine are among the 25 members of the Tuberculosis Drug Accelerator (TBDA), a network of academic, pharmaceutical, governmental, and other organizations that work collaboratively to gain a better understanding of the disease and design high-impact drug candidates. TBDA members share compound libraries and data, while working together to develop the best prospects, regardless of where the candidate originated.