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Computer Simulation May Shape Antibiotics of the Future

British research focused on the role of enzymes in bacteria

Scientists in the United Kingdom have used computer simulations to show how bacteria are able to destroy antibiotics — a breakthrough that will help develop drugs to tackle infections effectively in the future.
Researchers at the University of Bristol focused on the role of enzymes in the bacteria, which split the structure of the antibiotic and stop it from working, making the bacteria resistant. The new findings, published in Chemical Communications, show that it’s possible to test how enzymes react to certain antibiotics.
It’s hoped this insight will help scientists develop new antibiotics with a much lower risk of resistance and choose the best medicines for specific outbreaks.
Using a technique called quantum mechanics/molecular mechanics (QM/MM) simulations, the Bristol research team was able to gain a molecular-level insight into how enzymes called beta-lactamases react to antibiotics.
Researchers specifically want to understand the growing resistance to carbapenems, which are known as the “last resort” antibiotics for many bacterial infections and super-bugs such as E. coli. Resistance to carbapenems makes some bacterial infections untreatable, resulting in minor infections becoming very dangerous and potentially deadly.
The QM/MM simulations revealed that the most important step in the whole process is when the enzyme “spits out” the broken-down antibiotic. If this happens quickly, then the enzyme is able to go on chewing up antibiotics and the bacterium is resistant. If it happens slowly, then the enzyme becomes clogged and can't break down any more antibiotics, so the bacterium is more likely to die.
The rate of this “spitting out” depends on the height of the energy barrier for the reaction — if the barrier is high, it happens slowly; if it's low, it happens much more quickly.
“We've shown that we can use computer simulations to identify which enzymes break down and spit out carbapenems quickly and those that do it only slowly,” said Professor Adrian Mulholland of Bristol University’s School of Chemistry. “This means that these simulations can be used in future to test enzymes and predict and understand resistance. We hope that this will identify how they act against different drugs — a useful tool in developing new antibiotics and helping to choose which drugs might be best for treating a particular outbreak.”
The research, carried out by academics and postgraduate and undergraduate students in the School of Chemistry and the School of Cellular and Molecular Medicine, was funded by the Engineering and Physical Sciences Research Council.
Source: University of Bristol; October 17, 2014.

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