Treatment search

A better antibiotic for the treatment of tuberculosis | News

May 12, 2022 – In the last years of his doctoral research, Harim Won laid the foundation for the development of a new type of antibiotic to treat tuberculosis (TB), tackling the long-standing problems of long treatment and antibiotic resistance. Won uses a new approach to turn a normal protein system in the bacterial cell against itself.

Won, who works in the lab of Eric Rubin, assistant professor of immunology and infectious diseases at the Harvard TH Chan School of Public Health, is completing a degree in biological sciences in public health.

In January, Won was named a 2022 Harvard Horizons Scholar by the Graduate School of Arts and Sciences. Selected for his promising research, he had the opportunity, along with the other seven Horizons fellows, to share his work during a public symposium in mid-April.

Since TB treatment lasts from six months for typical cases to two years for multidrug-resistant cases, health workers visit patients’ homes every day to ensure that antibiotics are taken regularly. The COVID-19 pandemic has disrupted this process, particularly in low- and middle-income countries with limited resources. As a result, after years of steady declines in TB deaths, the trend has reversed.

The conventional strategy of finding more effective antibiotics has had limited success in recent decades. “If you think of a bacterial cell as an electric pencil sharpener, one of the bacterial proteins could be compared to the blades of the pencil sharpener,” Won explained. “If you took Silly Putty and stuck it directly into the blades, it would stop that component from working and the sharpener wouldn’t work, like the bacteria cell that would die if an antibiotic molecule blocked the protein. Instead, what if we could somehow make the sharpener chew its own wiring?”

Since a traditional antibiotic molecule inserts into a specific site on the protein, a single mutation can prevent binding and lead to drug resistance.

Won looked to other fields for inspiration, taking an approach called targeted protein degradation that has been used to create cancer drugs. Adapting the strategy to bacteria, instead of an antibiotic molecule stuck to a bacterial protein, the method uses a two-headed molecule that binds to both a target protein and a protein system called a protease. “We can think of a protease as garbage in the cell. Its tasks include chewing old proteins or those that are spoiled for one reason or another. With targeted protein breakdown, you’re taking a normal system in cells and redirecting it to destroy disease-causing proteins,” he said.

Compared to a traditional antibiotic, the two-headed molecule can theoretically attach anywhere on the target protein and protease, not just one site, giving researchers more options for drug design and control. against antibiotic resistance.

In proof-of-concept experiments, Won used genetic engineering techniques to modify potential target proteins and protease. He added beacons that brought the two parts closer together inside the cell, mimicking the role of the double-headed molecule. He discovered that protease could indeed degrade target proteins and affect bacteria, either by reducing bacterial growth or by making bacteria more sensitive to an existing antibiotic.

Won performed the experiments in a petri dish using a bacterial strain that models tuberculosis. The next steps therefore include tests using tuberculosis bacteria and animal models of the disease. Once the experiments identify the best target proteins, the lab will work with chemists to find a molecule that binds to the proteins and the protease.

“Our approach to developing new antibiotics is very much about trying to find ways to erase the works of the body that cause infection,” Rubin said. “Harry is taking a very different path, turning an essential bacterial system against itself. This opens up a whole new path towards the development of anti-infective drugs.

More broadly, Won views antibiotic development as a matter of justice. “Exposure is not equal in infectious diseases, nor is access to treatment equitable. The best way I can think of to make our world a healthier place is to be part of the process of making new medicines that help people,” he said.

Watch a video clip of Harim Won’s Harvard Horizons Symposium presentation

-Jessica Lau

Photo: Kent Dayton