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A bacterial enzyme releasing fragments of clavulanic acid, a resistance blocker designed to overcome antibiotic resistant infections. Destroying clavulanic acid enables the enzyme to protect bacteria from the effects of antibiotics. Photo: Marc van der Kamp

Through computer simulations, scientists can predict if bacteria can be stopped with popular antibacterial therapies or not. This technology is a breakthrough that will help select and develop effective treatments for bacterial infections.

Growing resistance to antibiotics is one of the most serious global health threats that the world is facing.

There is an urgent need to develop new antibiotics that are cost effective as it is estimated that by 2050, 10 million lives per year will be at risk from antibiotic-resistant infections.

In a bid to help tackle this challenge, researchers at the University of Bristol have developed computer simulations that could be key to getting ahead in the ongoing arms race with bacteria.

Researchers focused on enzymes in bacteria that can split the structure of penicillin-type antibiotics, leading to resistance.

To restore the effectiveness of these antibiotics, resistance blocking molecules have been developed to block the activity of these enzymes. By treating patients with the right combinations of antibiotics and resistance blockers, doctors are able to gain the upper hand in the battle.

Unfortunately, bacteria can make many different enzymes able to destroy penicillins, and resistance blockers that are available only work against some of these.

New findings, published in Biochemistry, show that it is now possible to use computer simulations to predict whether these resistance blockers will be effective or not.

It is hoped that this information will help scientists to develop improved resistance blockers that can restore the action of popular antibiotics against a wider range of resistant bacteria.

Using a computer simulation technique called QM/MM, which stands for Quantum Mechanics/Molecular Mechanics simulations, the research team was able to gain a molecular-level insight into how resistance enzymes react with resistance blockers.

Researchers specifically focused on clavulanic acid, a drug that prevents destruction of common penicillin-like antibiotics.

Clavulanic acid is commonly used in combination with the antibiotic amoxicillin to treat ear, sinus and urinary tract infections (co-amoxiclav.)

However, some bacterial infections are becoming much more difficult to treat because clavulanic acid does not work effectively against the enzymes that they produce.

The QM/MM simulations interrogated how clavulanic acid interacts with these bacterial enzymes and revealed the most important step in determining whether the enzyme is effectively blocked. An enzyme that cannot be stopped releases a broken-down molecule of clavulanic acid and goes on to break down the antibiotic that it is administered with, resulting in antibiotic resistance. If the breakdown of clavulanic acid takes a long time, the enzyme gets clogged up and is unable to break down the antibiotic, that can then kill the bacterium and clear the infection.

"We are excited to see how our computer simulations can be used in the future to test enzymes from bacteria and predict when a resistance blocking inhibitor will be effective," Marc van der Kamp, from the University's School of Biochemistry, said." We hope that this will identify how we can better block such bacterial enzymes, so that antibiotics can be used effectively for treatment of drug resistant infections. Our simulations may also be a valuable tool to help choose which combinations of drugs are best for treating a particular infection outbreak, allowing us to be better equipped in this arms race with bacteria."

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