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Biomedical engineers' detective work reveals antibiotic mechanism
Date:11/17/2008

sed on finding the trigger that set the radical-producing pathway snowballing. They made extensive maps of which genes turned on and off when they subjected E. coli bacteria to antibiotic treatment. Within the category of antibiotics studied, some kill bacteria outright, and produce deadly hydroxyl radicals, while other drugs of the class don't trigger hydroxyl radical-production and merely stop bacterial growth.

Using a unique approach, akin to the Sunday comics game asking players to find subtle differences in two nearly identical pictures, the researchers carefully compared the changes in E. coli gene expression caused by these two types of antibiotics. They found a few clusters of genes acting differently when the more powerful drugs were used. These differences provided the hints the team needed to discover how these antibiotics specifically triggered hydroxyl radical production.

The researchers found that the gene clusters of interest controlled jobs within the cell including trafficking proteins to the cell membrane and stress response systems that changed cell metabolism. They then worked out the series of events, that featured misfolded proteins and molecular relay teams that linked these pieces of evidence.

The pathway begins with the antibiotic entering a bacterial cell and attacking ribosomes, the submicroscopic protein-making agents inside all cells, which led to the production of misfolded proteins. Collins group's pathway picks up from there. These deformed proteins get delivered to the cell membrane, and the cell is quick to notice the changes. The bacteria's two-component molecular emergency systems work like a smoke alarm, first detecting the abnormality and then responding to it. The alarm signal is rapidly relayed to the bacterial cell's stress response machinery, which throws the cell into a frantic state, causing it to over-produce hydroxyl radicals, contributing to the cell's death.

These findings o
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Contact: Ronald Rosenberg
ronrosen@bu.edu
617-358-1240
Boston University
Source:Eurekalert

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