Institute, GlaxoSmithKline ID Tuberculosis Candidates

Tuberculosis bacteria (DoE.gov)

13 October 2015. A biomedical research institute partnered with a lab backed by pharmaceutical company GlaxoSmithKline to identify candidates for drugs that act on bacteria causing tuberculosis. The team from Center for Infectious Disease Research in Seattle and Tres Cantos Open Lab Foundation, a lab in Spain sponsored by GlaxoSmithKline, published its findings in a recent issue of the journal ACS Infectious Diseases (paid subscription required).

The researchers, led by the Center’s David Sherman, are seeking new kinds of drugs to treat tuberculosis, a bacterial disease that continues to inflict a heavy burden worldwide. While the global number of tuberculosis cases is falling, World Health Organization reports in 2013, some 9 million new cases of tuberculosis with 1.5 million deaths. Many of the cases occur in people with HIV, with 360,000 deaths in 2013 reported among people who are HIV-positive.

A key problem in eradicating tuberculosis is the ability of the pathogen Mycobacterium tuberculosis to become resistant to many antibiotics given to patients. This resistance often arises from the lengthy course of treatment, about 6 months, patients are required to follow. For many patients, symptoms disappear after a few weeks, which tempts them to discontinue taking their medications. As a result, the tuberculosis pathogen remains in the body and builds a resistance to the drugs.

Sherman and Center colleague Anuradha Kumar investigated antifolate compounds for their activity against Mycobacterium tuberculosis. Antifolates are already in use to treat some forms of cancer, and other bacterial, fungal, and parasitic infections. While Sherman and Kumar amassed considerable expertise on these compounds that block activity of folic acid and kill cells, they asked the Tres Cantos lab for help, specifically for access to GlaxoSmithKline’s extensive drug chemistry library.

GlaxoSmithKline’s library made it possible for Sherman and Kumar to screen for a particular type of compound, dihydrofolate reductase inhibitors limiting activity of enzymes that synthesize thymidylate, a nucleic acid in DNA. At Tres Cantos, the team started with 2,508 antifolate compounds, and after tests with live tuberculosis bacteria winnowed the list to 210 compounds. Further tests narrowed the list to 5 finalists, each of which exhibited potency against the bacteria.

Their investigation led to one particulate type of compound, analogues of the chemotherapy drug methotrexate, administered in advanced or serious cancer cases. The drug is also given for severe psoriasis and rheumatoid arthritis. In a Center statement, Sherman says the team’s “next steps are to expand the chemistry around these molecules to identify compounds that could ultimately be administered effectively in humans” adding, “These compounds could literally be lifesavers for millions of people.”

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