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The University of Southampton

Breaking down antibiotic resistance

Using supercomputers and simulations to find solutions and fight infections

20 March 2018

In 2017 the Office for National Statistics stated that antibiotic resistance has caused a fall in life expectancy for the first time. If nothing changes, by 2050 infections and illnesses that would previously have been curable by antibiotics will kill more people worldwide than cancer.

Bacteria are becoming resistant to antibiotic treatment thanks to overuse on a global scale. Taking these drugs indiscriminately to treat non-serious infections, coupled with excessive use in agriculture, means that the bacteria are now learning new ways to fight back, and we are facing a serious threat from infections that are gradually becoming harder to treat, such as pneumonia and tuberculosis.

Syma Khalid, Professor of Computational Biophysics, explains that bacteria have evolved to protect themselves against our medicine.

“The misconception people have is that it is us who become resistant; but it is not the people, it is the bacteria,” she says.

“The resistance we are seeing is a survival mechanism. It is just evolution, but theirs happens on a much faster timescale because of their short lifespan. They are always going to be one step ahead, and now these bacteria are fighting back against antibiotics.

It’s like they’ve developed a new, stronger coat of armour and we need new weapons now.

Professor Syma Khalid - Professor of Computational Biophysics

Bridging the gap between computer and biological science

We are seeing an increasing number of marketing campaigns designed to raise awareness of the issue and to encourage a change in habits, aiming to prevent overuse of antibiotics and unnecessary prescription. Researchers at Southampton are working on many exciting, different ways to fight antibiotic resistance from the very root of the problem.

Syma and her team are one of these groups, bringing computer graphics and coding together with biology and chemistry through computational chemistry to delve into the structure and processes within the bacteria themselves.

Computational chemistry methods use computer simulation alongside theoretical chemistry to solve problems, predict outcomes, and complement experiments taking place in laboratories. Using these methods ­– which are popular in the world of drug design – enables researchers to conduct otherwise difficult experiments in a safe environment, and can be used to explain and explore new and unknown chemistry even further.

Syma and her research group create accurate computer models of molecules and biophysical systems in order to better understand how they work. In the world of antibiotic resistance, for example, they can use computers to examine exactly how bacteria repel or destroy antibiotics, and how we might be able to tackle this in order to create new, successful drugs.

Working outside of the laboratory in this novel way gives scientists the ability to study more closely how the mechanics of molecules, such as those found within bacteria, work through creating computerised simulations of the bacteria, and testing hypotheses and concepts.

“Computational chemistry allows you to see things you might not ordinarily be able to see otherwise,” says Syma. “That’s why some people have started calling it the ‘computational microscope’, which I quite like. It lets you zoom in and see things more clearly.”

Breaking down the defence

Antibiotics can work in one of two ways; by either destroying the membrane of the bacteria, which subsequently destroys the cell, or by getting through the membrane and stopping the proteins from the inside.

It is the team’s job to use simulations and models developed from structural examination of these cells to assess where antibiotics are facing problems, and how exactly the bacteria are fighting back.

“You can think of it like this: the bacteria’s membrane is a fort, or the castle walls. You can either destroy the castle by making a massive hole in that wall, or by getting in without being seen and defeating the enemy from the inside,” explains Syma.

Bacteria know what to expect from our antibiotics, and they are able to protect themselves more easily. This can be in a number of ways; through expelling antibiotics through ‘pumps’, changing their membranes for protection, or by over-expressing proteins which can make it harder for the antibiotics to get through and destroy the cell.

The computational chemists work with a number of other experts and groups in an iterative process to inform the development of new antibiotics and alternative options. By collaborating with teams of structural biologists, computer scientists, mathematicians and biochemists, they can improve the accuracy of their simulations, inform experiments, predict outcomes and provide insight into the challenges facing scientists developing new and alternative antibiotics.

“It’s very synergistic. Every single project in my group involves an experimental group too. I don’t really believe in doing calculations in isolation,” says Syma.

There has to be some anchor in reality, and some feedback. You carry out a simulation and you report back to other teams and help them to inform their next experiments; it really is mutually beneficial.

Professor Syma Khalid - Professor of Computational Biophysics

International impact

Antibiotic resistance is a challenge on a global scale, and so research into combatting the problem is taking place internationally. Syma and her team are working with colleagues around the world, including America, the Netherlands, Canada and Australia.

Their international collaborations also reach India, where antibiotic resistance is a significant issue. India’s consumption of antibiotics is twinned with misunderstanding and unnecessary use; in a World Health Organization (WHO) survey in 2015, 75 per cent of respondents in India incorrectly thought that antibiotics could be used to treat colds and flu. However, a recent trip to the country uncovered some exciting results which could lead to major breakthroughs.

“There are Scientists in India who have discovered natural, novel compounds from plants that can’t be found in the UK. They think these compounds can be used as antibiotics. It is my job to complete some simulations for them, and see how they behave in our model membranes.

“We plan to complete this work with Public Health England, along with our connections with other UK institutions and partners in India. It’s very exciting,” she says.

Harnessing the supercomputer

Computer simulations on this scale would not be possible without the right technology. Thanks to facilities at Southampton, Syma and her team have an edge in the computational chemistry world. Our supercomputing facility, Iridis, is one of the top supercomputing sites in the UK, access to which gives Syma and her team a head start in their research.

“Without these facilities, we couldn’t do what we do. It’s a major reason why I’m here,” she says.

“Typically the calculations we do in my research group are on a large scale, which is not the norm in computational chemistry, but it’s made possible by being at Southampton. Things that take me a few weeks to do will take colleagues at other universities maybe months, so we have a real advantage.”

Using this technology means that computational chemists like Syma play a key role in revealing more about antibiotic resistance and in discovering solutions.

“If we’re going to design new antibiotics, rather than just taking shots in the dark or making random changes to molecules in a rational way, we need to know what we’re aiming for.

“We need to find not just new antibiotics, but new strategies”

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