Scientists at the Center for Infectious Disease Research, the largest independent nonprofit in the US focused solely on infectious disease research, partnered with the Tres Cantos Open Lab Foundation at global pharmaceutical company GlaxoSmithKline (GSK) to advance critically-needed treatments for Mycobacterium tuberculosis (Mtb). The research conducted through the partnership indicates that antifolates may be a candidate for continued tuberculosis drug discovery.
“With tuberculosis killing 1.5 million people every year and current drugs diminishing in their effectiveness, this antifolate research is critical for finding new ways to treat TB,” said David Sherman, Ph.D., a professor at the Center for Infectious Disease Research.
Dr. Sherman and fellow Center for Infectious Disease Researcher Anuradha Kumar, Ph.D., collaborated with GSK to combine the scientific expertise of academia with the vast infrastructure, resources and drug discovery know-how of a global pharmaceutical company.
Through the partnership, researchers curated a focused library of 2,508 potential antifolates, compounds that block production of folic acid and kill cells. The antifolates were then tested for activity against live Mtb and 17 active compounds were identified. The research revealed one antifolate is especially potent against Mtb, with numerous drug-like properties.
“The partnership with GSK was critical to the success of this project,” said Dr. Sherman. “We thought we could identify antifolates with strong activity on Mtb, but we needed to collaborate with a leading edge pharmaceutical company to actually find them.”
Currently, antifolates are typically used in cancer chemotherapies and to treat bacterial, fungal, and parasitic infections. There is also an approved antifolate used to treat the mycobacterial infection causing leprosy. However, work from the Sherman Lab and the Center for Infectious Disease Research demonstrated that analogues of the antifolate cancer chemotherapeutic methotrexate dramatically improved activity against TB in culture.
“Our next steps are to expand the chemistry around these molecules to identify compounds that could ultimately be administered effectively in humans,” said Dr. Sherman. “These compounds could literally be lifesavers for millions of people.”