Using a special profiling technique, scientists at Princeton University have determined the mechanism of action of a potent antibiotic, known as tropodithietic acid (TDA) (image), leading them to uncover its hidden ability as a potential anti-cancer agent. TDA is produced by marine bacteria belonging to the roseobacter family, which exist in a unique symbiosis with microscopic algae. The algae provide food for the bacteria, and the bacteria provide protection from the many pathogens of the open ocean. "This molecule keeps everything out," said Mohammad Seyedsayamdost, Ph.D., an Assistant Professor of Chemistry at Princeton and corresponding author on the study published online on January 22, 2016 in PNAS. "How could something so small be so broad-spectrum? That's what got us interested," he said. The PNAS article is titled “Mode of Action and Resistance Studies Unveil New Roles for Tropodithietic Acid As an Anticancer Agent and the -Glutamyl Cycle As a Proton Sink.” In collaboration with researchers in the laboratory of Zemer Gitai, Ph.D., an Associate Professor of Molecular Biology at Princeton, the team used a laboratory technique referred to as bacterial cytological profiling to investigate the mode of action of TDA. This method involves destroying bacterial cells with the antibiotic in the presence of a set of dyes, and then visually assessing the aftermath. “The key assumption is that dead cells that look the same probably died by the same mechanism,” Dr. Seyedsayamdost said. The team used three dyes to evaluate 13 different features of the deceased cells, such as cell membrane thickness and nucleoid area, comprising TDA's cytological profile. By comparing TDA’s profile to those for other known drugs, the researchers found a match with a class of compounds called polyethers, which possess anti-cancer activity.
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