Scientists notch a win in war against antibiotic-resistant bacteria

February 4, 2013, Harvard University
Scientists from the Wyss Institute at Harvard University and Boston University interfered with the metabolism of E. coli, rendering them weaker in the face of existing antibiotics, as reported today in Nature Biotechnology. Credit: Wyss Institute at Harvard University

A team of scientists just won a battle in the war against antibiotic-resistant "superbugs"—and only time will tell if their feat is akin to the bacterial "Battle of Gettysburg" that turns the tide toward victory.

They won this particular battle, or at least gained some critical intelligence, not by designing a new antibiotic, but by interfering with the metabolism of the bacterial "bugs" – E. coli in this case – and rendering them weaker in the face of existing antibiotics, as reported today in .

It's the "kick 'em when they're down" style of fighting, and the team from Harvard's Wyss Institute for Biologically Inspired Engineering and Boston University used sophisticated computer modeling and biotechnology as their weapons of choice.

"We are in critical need for novel strategies to boost our antibiotic arsenal," said senior author and Wyss Core Faculty member Jim Collins, Ph.D., a pioneer of synthetic biology who is also the William F. Warren Distinguished Professor at Boston University, where he leads the Center for BioDynamics. "With precious few in the pipeline, we are finding new ways to harness and exploit certain aspects of bacterial physiology."

In this case, the team targeted a little understood but key part of bacterial metabolism called ROS production.

ROS, or "," include molecules like superoxide and that are natural byproducts of normal . Bacteria usually cope just fine with them, but too many can cause serious damage or even kill the cell. In fact, Collins' team revealed a few years ago the true antibiotic "modis operandi": they kill bacteria in part by ramping up ROS production.

The precise by which E. coli produces ROS remain elusive, Collins said, so his team adopted a standard computer model that maps out the way scientists currently understand E. coli metabolism. Collins' team began by adding to this "system-level" metabolic model hundreds of reactions that are known to increase ROS production. Then they deleted various genes to see which were involved in ROS production, honed in on the suspected targets after running thousands of computer simulations, and validated the model in the laboratory—achieving 80-90% agreement with the model-based predictions.

"The next challenge was to determine if increasing the ROS production by the cell itself would render it more susceptible to death by oxidative, ergo, antibiotic attack," Collins said—and it did. The team deleted a series of genes that led to increased ROS production in the cell, added different antibiotics and biocides such as bleach – known cell-killers by way of increasing ROS production – and the cells died at a much higher rate than the cells without the deleted genes. In short, by interfering with the bacterial metabolism, the antibiotics and biocides were even more lethal to the cells.

"There is no magic bullet for the global health crisis we're experiencing in terms of antibiotic-resistant bacteria," said Don Ingber, M.D., Ph.D., Wyss Founding Director, "and yet there is tremendous hope in the kinds of pioneering systems biology approaches Jim and his team are spearheading."

The team's next steps are to use molecular screening technologies to precisely identify molecules that boost ROS production, Collins said, and to test the approach used in this E. coli study on other kinds of bacteria—such as the mycobacteria responsible for tuberculosis, a potentially lethal lung disease.

Explore further: Antibiotics as active mutagens in the emergence of multidrug resistance

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4.7 / 5 (3) Feb 04, 2013
I see a small problem with this method of fighting infection. How do they propose to modify the genome of the bacteria that are already infecting someone?

But seriously, the more we can hurt bacteria, the better. They just need to find ways to boost ROS production chemically rather than genetically.
1 / 5 (1) Feb 04, 2013
Why not just do it in a simple and effective manner without pharmaceutical assistance? e. g.:
2.6 / 5 (10) Feb 04, 2013
With the overprescribing of antibiotics, we'll be seeing more superbugs. This is fantastic news, though!
1 / 5 (1) Feb 04, 2013
We have underestimated the adaptability of bacteria before. IMHO, any new battleground technique like this should be studied in the lab for years before it is released to the general public. Yes, I understand that we need discoveries like this to fight "the war," however, if we end up making even more of a superbug because of lack of laboratory analysis, then shame on us.
1 / 5 (4) Feb 04, 2013
Don't be too proud of this anti-biotic terror you've constructed.

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