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Buying time: the fight against antibiotic resistance (Nonesuch autumn 2015)

Scientists peering at hourglass

Chris Madden

Chris Madden

Petri dish

Chris Madden

6 November 2015

Over the next 35 years, 300 million people are expected to die prematurely because of resistance to antibiotics*. So why aren’t new drugs coming to market, and are there other, better ways to tackle infection? Nonesuch spoke to alumni and University researchers to find out.

Imagine a world in which a scratched knee could leave you fighting for your life. Existing treatments for tuberculosis and pneumonia are no longer effective, and whole areas of modern medical practice, from routine operations to chemotherapy, carry the risk of fatal infection. Healthcare systems have buckled under rising mortality rates; the cost to the global economy is devastating.

Life in a ‘post-antibiotic’ era might sound like the stuff of science fiction, but according to health experts, that world could soon become reality unless we can turn the tide on the ever-growing threat of antimicrobial resistance (AMR).

‘There are certainly mixed messages about how serious AMR is,’ says Dr Matthew Avison (BSc 1994, PhD 1998), Senior Lecturer in Microbiology at the University of Bristol. ‘We’re not all going to die imminently, as some of the headlines suggest. But nor do we have years before things get critical. Yes, it’s going to be a massive problem in 2050. But it’s also a pretty big problem now.’

As Avison points out, the media tends to focus on scenarios in which we’ve lost the ability to treat all types of infection. But the real worry, Avison explains, is that: ‘some infections are already untreatable with current drugs. Gram-negative bacteria like E. coli, for example, can be highly impermeable – it’s very difficult to get drugs into them. Yet they’re the bacteria that account for the highest proportion of hospital-acquired infections.’

Strength in numbers

Understanding how bacteria develop resistance is a case study in evolution by natural selection. Bacteria are among the fastest reproducing organisms in the world: in the right conditions, some are able to duplicate every 20 minutes. They can also transfer genes horizontally – to surrounding bacteria as well as their offspring. So, only a few need to survive a treatment of antibiotics to pass that resistance on in a matter of hours, compared with the years it can take to bring an effective drug to market. And the more we use antibiotics, the more widespread resistance becomes.

Penicillin, tetracycline, methicillin – within a couple of years of the introduction of all these antibiotics, bacteria started to show signs of resistance. Now the pipeline of new drugs is effectively dry. Since the 1970s, only two new classes of antibiotics have been introduced, and neither is effective in treating gram-negative bacteria.

Dr David Brown (PhD 1975), whose 40-year career includes research roles at Zeneca, Pfizer, GlaxoSmithKline and Roche, explains: ‘Many pharmaceutical companies have closed down their antibiotic research divisions because they don’t make money. Antibiotics are only ever prescribed for a short course of treatment, while drugs for cancer, diabetes and heart disease can be prescribed for life. There’s a high rate of failure in this field, and any new discoveries wouldn’t be allowed broad marketing with high sales – they’d be held back as a "last line of defence" for the most lethal infections.’

Certainly, for the few companies that have kept up the search for new antibiotics, success continues to elude. Earlier this year, BBC’s Panorama reported that GlaxoSmithKline spent $1 billion on antibiotics research in the past decade – without bringing any new drugs to market. One drug came close, yet early signs of resistance appeared in the final stages of testing. ‘Companies simply can’t survive by pursuing that type of research,’ says Brown.

‘Even if we could incentivise them and throw more money at the problem, I’m not convinced we’d get results this way. Commercial approaches have failed to deliver: we have to start thinking differently instead.’

Brown is now a trustee of Antibiotic Research UK, a charity set up last year to harness AMR expertise across the UK and help fund the discovery of new therapies. ‘One area we’re working on is salvaging some of the drugs we’ve already got. We’re combining existing drugs that show signs of antibiotic activity, even though they’re used to treat other conditions like cancer or heart disease, to create drugs known as antibiotic resistance breakers. Using existing drugs removes some of the commercial barriers we face, as they’ve already been proven to be safe for use. I’m confident that if we can find one or two combinations that work, they’d make a big contribution to filling the current gap of effective treatments.’

‘Risky’ science

Thinking differently is also what AMR researchers at Bristol are doing thanks to a new initiative, BristolBridge. Funded by the Engineering and Physical Sciences Research Council, the initiative will support a wide range of short-term research projects that combine expertise from different academic disciplines.

‘BristolBridge is about giving researchers a chance to test completely new ideas,’ explains Professor Adrian Mulholland (BSc 1990), Principal Investigator for BristolBridge. ‘We’re looking for zany ideas – ideas that are completely off the wall – to test in the lab. Ninety per cent of the projects might only create knowledge about what won’t work. But the other ten per cent might be completely transformative.’

Bristol has a long tradition of AMR research in the field of microbiology: the University’s School of Cellular and Molecular Medicine was set up in the 1960s by Professor Sir Mark Richmond after hospitals detected the first strains of drug-resistant bacteria. Now, BristolBridge hopes to build on that tradition by looking at AMR from less conventional angles, by involving engineers, mathematicians and physical scientists in the search for solutions. ‘As academics, we’re all guilty of pursuing "one directional" science,’ admits Mulholland, ‘but you can get a really big pay-off by taking pre-existing knowledge from one field and using it in another context.’

Mulholland cites the recent discovery of a new antibacterial technology, Pertinax™, as a perfect example of this approach. Dr Michele Barbour (PhD 2003) originally developed Pertinax™ for use in the dental industry: one in seven fillings fail within seven years, usually because of bacterial infection. But now, through BristolBridge, Barbour is working with colleagues in engineering, mathematics and chemistry to explore whether Pertinax™ may also offer protection against infections acquired from hospital products, such as catheters, implants and wound dressings. ‘You probably wouldn’t expect academics based in dentistry and aerospace engineering to come up with a wound dressing,’ says Mulholland.

As well as bringing together academics within the University, BristolBridge also aims to forge links with other research institutions and industry partners to explore new lines of enquiry. 'One of the joys of science is collaborating,’ says Mulholland. ‘Nobody in the world knows the best way to tackle AMR at the moment. There’s been a huge focus on new drugs, but they’re not the only answer. We need a much broader approach: effective diagnostic tools, improved wound dressings, and a better understanding of how diseases interact and spread. Even little interventions, like changing the way a GP talks to patients, could make a huge difference.’

Doctor’s orders

The role of GPs in the spread of AMR has certainly come under increased scrutiny in recent months, as have practices within the farming industry, which accounts for 70 per cent of antibiotic usage in the UK. Patients need to take responsibility too: in most cases, antibiotics are wholly ineffective in treating colds and coughs, and finishing a course of drugs too early also increases the risk of bacteria developing and spreading resistance.

‘Slowing the rise of resistance will be almost as good as finding a new drug,’ explains Avison, who is also Impact Facilitator for BristolBridge. ‘It’s important that we work with clinicians: they know what the problems are now. But we also need to understand what impact changing current behaviour and practice could have in the future.’

Through BristolBridge, Avison, Mulholland and others hope to harness the power of Bristol’s high-performance computer, BlueCrystal, to fill that knowledge gap, quickly. Earlier this year, as part of a multinational study, a team led by Dr David Matthews, Senior Lecturer in Virology, used BlueCrystal to examine both how the Ebola virus evolved and how effective treatment and vaccination programmes would be at controlling the outbreak. ‘We can use computers to monitor how bacteria behave, and to predict how successful certain drugs would be against them,’ says Mulholland. ‘There’s also a huge amount of data still to be mined – data that we can use to model future scenarios and ultimately inform public health policy.’

‘To a certain extent, we have to keep running to stand still,’ adds Avison. ‘We have lost a lot of expertise in the field in recent decades, but we also now have new technologies at our disposal. I don’t think it will take a huge advance to turn the tide, but we have to accept that we might never win. Bacteria are adaptable. They’ve had billions of years to work on that.’

Seeking solutions

Experts across the University are contributing to the work of BristolBridge.

A team led by Professor Bo Su is looking at whether the structure of cicada wings could inspire ways to penetrate gram-negative bacteria. Cicadas use ‘nanospears’ to destroy bacteria through their physical, rather than their biological, structure.

Dr Andrew Collins and colleagues are exploring whether nanoparticles could hold the key to disease- and patient-specific diagnostic tests and treatments.

Dr Kristen Reyher is investigating what impact the use of antibiotics on farms has on bacteria that might transfer to people. Her team also hopes to establish whether reducing veterinary antibiotic prescriptions will help curb the rise of resistance.

Further information

In October, Dr Helen Lambert, Reader in Medical Anthropology from the University of Bristol’s School of Social and Community Medicine, was appointed to the new position of Anti-Microbial Resistance (AMR) Research Champion for the Economic and Social Research Council (ESRC).
 
Recent Chemistry graduate, Kate Hammond (MSci 2015) also won the William Edward Garner Prize - awarded to the best final-year MSci strudent in Chemistry - for her work on modelling beta-lactamases.