When Scott Franzblau began researching tuberculosis in the early 1990s, he had a hunch that the clarithromycin related macrolides he successfully tested for treating leprosy just might work for TB. His hunch paid off, opening research into an exciting new class of compounds for TB.
"The two diseases require very specific types of antibiotics, yet both suffer from a lack of resources for research and development," Franzblau says about the bridge between leprosy and TB. "I was drawn to these diseases precisely because I wanted to help fill the void in drug development for neglected diseases."
Armed with a TB Alliance grant, Franzblau is now devoting his full attention to investigating third generation macrolides and completing the transformation of a hunch into powerful TB therapies. His work has already developed several promising new drug leads.
"If we have something that looks interesting, the TB Alliance is the first organization I think of," says Franzblau, director of the Institute for Tuberculosis Research at the University of Illinois at Chicago. "Their work is critical – not only for its scientific contributions, but because they are completely committed to developing medicines that will actually get into the hands of patients in the developing world."
Franzblau’s work with leprosy frequently took him to the Philippines where he headed three clinical drug trials. While there, Scott first encountered the macrolide class of drugs and collected enough data to lead to his hunch about its efficacy for tuberculosis. After a decade of studying leprosy at the National Hansen’s Disease Center, Franzblau shifted his attention to tuberculosis. In 2000 a move to the University of Illinois Chicago gave Franzblau the opportunity to interact more closely with medicinal chemists and pharmacologists.
"I really wanted to make a contribution," he says. "It seemed for me that the best way to do that was to work on a neglected disease that continues to kill millions of people every year and that affects millions more."
It wasn’t long before he started his work with TB that Franzblau was testing his macrolide theory.
"Macrolides have a history of being very good for respiratory infections," he explains. "They get to the lung and work well and have been around for a long time with a good safety record."
Needing samples to test, Franzblau sent letters asking pharmaceutical companies for compounds that might be lying around unused. He didn’t get a single response. But Scott Franzblau is nothing if not determined. He eventually convinced a Japanese company to send macrolides and called upon his colleagues to send him their shelved pharmaceutical samples. To his delight some compounds showed encouraging activity against TB. Working with the third generation of compounds, Franzblau anticipates identifying a macrolide that is much more active against Mycobacterium tuberculosis and has already reached one milestone in his research – he has identified a macrolide that is highly active against TB and doesn’t inhibit the human cytochrome P450, the body’s major drug metabolizing enzyme. Some macrolides inhibit this process, which causes potential drug-drug interactions, including with HIV/AIDS therapies, and may lead to serious side effects in a combination therapy.
"This is a major issue with this class of drugs," Franzblau says. "But the Alliance goal that we find drugs that can be integrated in TB-HIV therapy is so important, that we are working to identify a macrolide that kills TB but doesn’t inhibit the cytochrome."
Franzblau’s team has also developed a lab test that can predict a new drug’s activity against dormant TB and is now using it to assist the Alliance in evaluating other compounds in their portfolio. Scientists are perplexed by the inability of the current drug arsenal to kill dormant TB and believe that because there are fewer replicating cells in dormancy, there are fewer targets for drugs to attack. Because dormant TB can eventually activate, scientists are searching for a drug that is deadly to both active and latent TB.
"We can now screen thousands of compounds to find out whether or not they have the ability to kill the TB bacterium in both its latent and active forms," he says. "We know that when we develop a drug that can efficiently kill the non-replicating bacteria, we can drastically shorten the length of TB treatment. That is the holy grail of TB drug research."