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.