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Modeling, Biotechnology Boost Antibiotic Impact on Pathogens

E coli bacteria magnified (ARS/Wikimedia Commons)

E coli bacteria magnified (USDA Agricultural Research Service/Wikimedia Commons)

Biomedical engineers at Harvard University’s Wyss Institute for Biologically Inspired Engineering combined computer modeling with biotechnology techniques to weaken resistance of E. coli cells to antibiotics. The team led by Jim Collins, with colleagues from Boston University, published its findings today online in the journal Nature Biotechnology, and filed a U.S. patent for the technology.

Collins and colleagues devised a method that changes the ability of Escherichia coli, or E coli, bacteria to adjust to increasing levels of oxygen molecules known as reactive oxygen species that are natural byproducts of the bacteria’s metabolism. E. coli can cope with small amounts of these reactive oxygen species, such as hydrogen peroxide, generated through their natural processes, but not in larger quantities that can damage or kill the organisms.

The genetic mechanism that governs these effects, however, are not well known, and the Wyss Institute team decided to use a computer model to capture what the researchers already knew about E. coli interactions with reactive oxygen species, and discover more about the genetic nature of these interactions. Collins’s team added to the model hundreds of reactions that are known to increase production of reactive oxygen species, and then through process of elimination, deleted various genes to discover the genes that affected reactive oxygen species production.

The model proved useful in predicting the genetic targets affecting reactive oxygen species or ROS production, which they validated in the lab, achieving 80 to 90 percent agreement between the model and lab tests. “The next challenge,” says Collins, “was to determine if increasing the ROS production by the cell itself would render it more susceptible to death by oxidative, ergo, antibiotic attack.”

The researchers genetically altered the E. coli, by removing genes that inhibited reactive oxygen species production during metabolism, making it possible, in effect, to increase the level of reactive oxygen species in the bacteria. The team then treated altered and regular E. coli with antibiotics and biocides such as bleach. The genetically altered E. coli — those with the limits removed on their reactive oxygen species — died at a much higher rate than the cells without the deleted genes.

Collins says he and his and colleagues next plan to apply molecular screening to precisely identify molecules that boost production of reactive oxygen species. They also expect to test their technique on other dangerous bacteria, such as the mycobacteria responsible for tuberculosis.

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