Scientists Weaken Superbugs By Interfering With Their Metabolism

Date: Feb-05-2013By Interfering With Their Metabolism

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Article Date: 05 Feb 2013 - 3:00 PST

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Scientists Weaken Superbugs By Interfering With Their Metabolism


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By interfering with their cellular metabolism, scientists in the US have found a way to weaken antibiotic-resistant bacteria, in this case
E. coli, so that they are once again susceptible to existing antibiotics.

The researchers, from Wyss Institute at Harvard University and Boston University, describe how they won this particular battle in the war against
superbugs, with weapons like sophisticated computer modeling and biotechnology, in a paper published online in Nature Biotechnology in
January.

Senior author Jim Collins, pioneer of synthetic biology and leader of the Center for BioDynamics at Boston University, says in a statement released
on Monday:

"We are in critical need for novel strategies to boost our antibiotic arsenal."

He refers to the antibiotics crisis, which has been brought to a head by renewed awareness that we are running out of drugs to treat evolving
superbugs.

"With precious few new antibiotics in the pipeline, we are finding new ways to harness and exploit certain aspects of bacterial physiology," says
Collins, who is also William F. Warren Distinguished Professor at Boston.
ROS Production
Collins and colleagues targeted a little understood but important area of bacteria metabolism known as "reactive oxygen species" or ROS
production.

ROS are normal byproducts of metabolism, the set of chemical reactions that keeps cells alive, allows them to grow, reproduce, maintain
themselves, and respond to their environments.

ROS include molecules like superoxide and hydrogen peroxide, which bacteria can normally cope with. But above certain levels, ROS molecules
can seriously damage and even kill bacteria.

In earlier work, Collins and his team had already established that this is how antibiotic kill off bacteria: they ramp up ROS production in the
bacterial cell, so in effect making the bug poison itself.
Computer Models of E. Coli Metabolism
But, it was not clear exactly how E. colli produces ROS. So Collins and his team decided to investigate using some sophisticalted computer
modeling.

They already had a computer model that mapped out the current understanding of E. coli metabolism, simulating some of the basic
chemical reactions involved.

So they started adding to this "system-level" model, hundreds more reactions that are known to increase production of ROS.

With painstaking precision, they deleted various genes, to see which ones took part in ROS production, and ran thousands of computer simulations,
before eventually identifying some suspected targets.

They validated the model in the lab, and found the lab experiments confirmed 80% to 90% of what they had predicted in the computer
simulations.
Increasing ROS Production in the Bacterial Cell Made It More Susceptible to Antibiotic Attack
The next step of the challenge was to test the results of the in silico experiment in real live bacterial cells. Would increasing ROS
production in the E. coli cells, render it more susceptible to death by oxidative, that is antibiotic, attack?

They found it did.

The researchers deleted a series of genes so as to ramp up ROS production in the cells, they added various antibiotics and other biocides or bug-killers like bleach (which also increases ROS production), and they found the E. coli cells died at a much higher rate than cells that
retained the deleted genes.

"This work establishes a systems-based method to tune ROS production in bacteria and demonstrates that increased microbial ROS production can
potentiate killing by oxidants and antibiotics," they write.

In other words, by disrupting the metabolism of E. coli cells, the scientists had made it easier for the antibiotics and biocides to kill them.
Implications and Next Step
Don Ingber, Founding Director of the Wyss Institute, says:

"There is no magic bullet for the global health crisis we're experiencing in terms of antibiotic-resistant bacteria."

But, he says there is "tremendous hope" in the kinds of systems biology methods that Collins and his team are pioneering.

The team is now planning to use molecular screening technologies to find specific molecules that boost ROS production.

They believe their approach will also help win battles against other bacteria, such as the mycobacteria responsible for tuberculosis, a potentially
lethal lung disease.

Funds from the Wyss Institute for Biologically Inspired Engineering at Harvard University, the National Institutes of Health Director's Pioneer Award
Program and the Howard Hughes Medical Institute, are helping to finance the team's research.

Written by Catharine Paddock PhD

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