Biomedical engineers' detective work reveals antibiotic mechanism

November 18, 2008

(Boston) -- A series of genetic clues led a team of Boston University biomedical engineers to uncover exactly how certain antibiotics kill bacteria. The findings could help rejuvenate the efficacy of older antibiotics and reveal new antibiotic targets within bacterial cells.

"The research speaks to new insights into how current antibiotics work and how those insights can point toward development of more effective antibiotics," said James Collins, Professor of Biomedical Engineering at Boston University.

He is the senior author of a paper in the November 14th issue of Cell which describes the details of this pathway, particularly the initial trigger of this deadly sequence of events.

Collins and his colleagues used systems biology approaches to identify clusters of genes that became more active in the bacteria treated with antibiotics. The researchers then reconstructed the series of events leading to antibiotic-mediated bacterial death, using the changes in these genes as clues.

"Modern tools allow the simultaneous analysis of the many interacting components that make up complex biological systems,'' said Jeremy M. Berg, director of the National Institutes of General Medical Sciences at the National Institutes of Health. "Using such a systems approach, Dr. Collins and his coworkers revealed a surprising mechanism of action for certain antibiotics. This lays the foundation for further antibiotic development -- a pressing drug development need." said Jeremy M. Berg, director of the National Institutes of General Medical Sciences.

Previously, Collins, Boston University doctoral candidate Michael Kohanski, and colleagues found a common mechanism of cell death in bacteria. They reported that several different classes of antibiotics all had this same underlying pathway that caused over-production of hydroxyl radical molecules which contributed to bacterial cell death.

The group's new research focused 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 open up new possibilities in fighting the looming specter of antibiotic resistance in bacteria. Knowing some of the specific differences between antibiotics that kill bacteria and those that have a weaker effect could allow researchers to transform the weaker antibiotics into more potent ones. This may bring some antibiotics with fading utility back into the limelight to fight infections, noted Collins.

The molecular alarm systems may also present new targets for antibiotic drugs. Historically, drugs have aimed their destructive powers at important cellular functions in the bacteria -- such as the ribosomes that translate genetic information. In revealing this new array of peripheral players in the bacteria's function, the Collins team has uncovered new drug targets. Creating drugs that attack these molecular alarms could help cripple the bacteria and, coupled with an older antibiotic, deliver a fatal blow.

"A lot of drug development has focused on targeting something that's important for the cell to live -- something essential," said Kohanski. "But if you understand the system and its complexity, you don't necessarily have to hit the gene or the protein that is the essential factor."

Boston University

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