Satellite images of Emiliania huxleyi blooms. Credit: NASA images
Using a special profiling technique, scientists at Princeton have determined the mechanism of action of a potent antibiotic, tropodithietic acid (TDA), leading them to uncover its hidden ability as a potential anticancer 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 Assistant Prof. Seyedsayamdost. “How could something so small be so broad spectrum? That’s what got us interested,” he said. The team used a lab technique: 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,” he said.
They used 3 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 to profiles of known drugs, the researchers found a match with a class of compounds called polyethers, which possess anticancer activity. They observed its strong anticancer activity in a screen against 60 different cancer cell lines. “The strength of this profiling technique is that it tells you how to repurpose molecules,” Seyedsayamdost said.
The researchers were surprised by the compounds’ shared mode of action because unlike the small sized TDA, polyether compounds are quite large. But through different chemical reactions, they are both able to cause chemical disruptions in the cell membrane that render the bacterium unable to produce the energy needed to perform critical tasks, eg cell division and making proteins.
They also wanted to know the mechanism by which a bacterial strain could become resistant to the antibiotic, especially how roseobacter kept itself safe from the antibiotic weapon that it produced. They probed the genes in roseobacter that synthesize TDA as well as surrounding genes. They identified 3 nearby genes responsible for transport in and out of the cell, and upon transferring these genes to E. coli, were able to produce an elusive TDA resistant bacterial strain.
“We often look at natural products as black boxes,” said Seyedsayamdost, “but these molecules have evolved for millennia to fulfill a certain function. By linking the unusual structural features of TDA to its mode of action, we have begun to explain why TDA looks the way it does.” http://www.eurekalert.org/pub_releases/2016-02/pu-aks020416.php
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