Battling superbugs with the power of knowledge

In the last 60 years mankind has come to rely on the wonder-cure of antibiotics to solve a multitude of ills by inhibiting disease-causing bacteria and curing potentially fatal infections.

However, misuse of antibiotics can lead to some bacteria becoming immune to the effects of antibiotics, stopping us getting better. This is known as anti-microbial or antibiotic resistance.

The O’Neill Report on anti-microbial resistance published in May 2016 highlighted that unless the world acts to tackle this issue now, by 2050 there could be up to 10 million deaths due to infections that are non-responsive to antibiotics.

Already, today, an estimated 700,000 deaths worldwide are related to anti-microbial resistance. The report identified that overuse of antibiotics is driving resistance.

As bacteria become resistant to a rapidly increasing number of the currently available antibiotics, and new cures become more difficult to find, the World Health Organisation has declared 14-20 November as World Antibiotic Awareness Week to keep international focus on the issue.

Dr Chris van Tulleken explains antibiotic resistance (Courtesy Public Health England and Antibiotic Guardian).

Individuals can take action to help control the spread of resistant bacteria, and many organisations contribute research, funding and knowledge towards the effort to create new drugs, and control those already in use to limit the occurrence and the spread of resistant bacteria.

Tackling the global challenge 

Among them, the University of Leeds is determined to play a key role, as part of its commitment to engaging in world leading research which impacts on the great issues we face.

Professor Mark Wilcox, from the University’s Faculty of Medicine and Health, plays a vital role at national and international levels as Chair of a Public Health England's Rapid Review Panel, which grades  the usefulness of infection prevention and control products for the NHS.

He is also Deputy Chair of the Department of Health’s advisory committee on Antimicrobial Resistance and Healthcare Associated Infection.

At Leeds, Professor Wilcox heads a Healthcare Associated Infection research team of 30 doctors, scientists and nurses studying antimicrobial resistance and the clinical development of new anti-microbial agents. 

Professor Christoph Wälti, from the Faculty of Engineering at Leeds, is another leading researcher tackling antimicrobial resistance. He says resistance to antibiotics can spread around the world much more quickly than people may expect.

“We live in a global society, people travel a lot and when you look at maps of how a resistant bacteria travels from A to B it moves very quickly.”

“It can be as little as months or maybe a year for a resistance to a certain antibiotic to occur in different parts of the world. We live in a global society, people travel a lot and when you look at maps of how a resistant bacteria travels from A to B it can move very quickly", he continued.

Knowledge through time and dedication

As far back as 1996, the University founded the Antimicrobial Research Centre in response to the growing problems of bacterial resistance to antibiotics.

Work in the 90s on the molecular basis of bacterial resistance to existing antibiotics was carried out to provide opportunities to circumvent resistance at the molecular level. This work laid the foundations for much of the University’s modern research leadership in this area.

In the 1970s and 1980s, new antibiotics were being discovered frequently which meant as one drug lost its bacteria-busting capability, so another came along which attacked bugs in a different manner.

Now though, scientists including Professor Wälti say the process for creating new drugs has slowed and few new antibiotics are expected to become available in the near future.

Super-fast diagnosis

A new five-year project at the University will contribute to reducing dramatically the time taken to diagnose different types of infection. This will be done by more rapidly determining whether a virus rather than a bacterium is responsible for some patients' symptoms. A new test could be used to avoid unnecessary antibiotic prescribing and so reduce the pressure for resistance development.

In May 2016, the University secured a £3.8million grant funded by the Antimicrobial Resistance Cross Council Initiative, which is a collaboration of all seven UK research councils, to carry out this work.

Experts from the Faculties of Medicine and Health, Engineering, and Biological Sciences are collaborating on the project.

It will result in a portable device which can be used in GP surgeries or at the bedside. It will contain complex sensors to diagnose within 10 minutes whether a patient is suffering from a disease caused by a virus or by bacteria. Currently, similar tests can take many hours.

With evidence available much more quickly, GPs or A&E doctors could treat patients using drugs they know are effective to treat an individual's illness.

Dr Lars Jeuken, one of the co-investigators on the project said: “When tests take too long, and patients put doctors under pressure, incorrect or unnecessary drugs can be given. However, wrongly prescribed drugs can have side effects. We hope improved quality and speed of diagnoses will make a significant difference.”

“We hope improved quality and speed of diagnoses will make a significant difference.”
DR LARS JEUKEN

Connecting biology with electronics

Dr Jeuken explained that key to cutting down the timescale for accurate diagnoses will be the development of new molecules which can bind biological samples to electronic sensors within the device, to produce a signal which can be read and used by medical staff.

The technology will integrate electronics with biological molecules and fluidics, relying on the expertise of Professor Nik Kapur and colleagues from the Faculty of Engineering.

This relationship takes place at the molecular level using ‘capture molecules’ that bind to ‘marker’ molecules present in the body as a result of an infection.

New artificial antibodies called Adhirons developed by Professor Mike McPherson and Dr Darren Tomlinson from the Faculty of Biological Sciences will be adapted for use. The University has licensed these molecules to Avacta Life Sciences as part of its Affimer platform.

Testing and validation of the new technology will be carried out by clinicians including Professor Wilcox, Dr Jonathon Sandoe and Dr Andrew Kirby, working in the Faculty of Medicine and Health, Leeds General Infirmary and at St James' Hospital. They will ensure lab-based trials can be reproduced in a clinical laboratory setting.

 Dr Michael Messenger will be involved in testing the device for clinical use.

The Leeds Diagnostic Evidence Co-Operative led by Dr Michael Messenger, will oversee the translation of the technology from the university’s labs into medical use.

Combatting Clostridium Difficile

As well as being a rapid test for many well-known infections, the technology will be specifically designed for use by hospital-based medics dealing with potential Clostridium Difficile infections (CDI). This will draw on the world-leading work carried out by the Professor Wilcox in this field.

The intention through this strand of work is to use the same device to detect whether the patient’s symptoms are indeed a result of CDI, so they can be treated with an appropriate antibiotic.

Viewpoint

Professor Christoph Wälti is leading the research.

Professor Christoph Wälti is the principal investigator in the project to create the portable testing device:

“A lot of people go to the doctor for antibiotics with common cold symptoms, but antibiotics will not help all of them, because the cause of their illness is not bacterial; it may be viral or fungal.

“What we are trying to do is create a diagnostic platform which can say very quickly that either the patient has an infection which can be treated with antibiotics, or another infection which cannot.

“The issue worldwide, which the O’Neill Report identified, is that overuse of antibiotics is driving anti-microbial resistance.

“The intention is for GPs and primary care providers to reduce significantly the number of antibiotic prescriptions. Doctors say they want something which can prove to patients that they do not have a bacterial illness, so they do not have to prescribe unneeded drugs.

“Existing diagnostic technology has limitations, which include sensitivity and the time to produce a verdict. We are developing the next generation of such technology to address the huge challenge of AMR.

“The key to this whole project is we have everything we need in place; there is a natural relationship between the people, the research and the infrastructure here at Leeds, which is so vital to making this happen."

The investigators in the project are: Professor Paul Millner, Professor Michael McPherson, Dr Lars Jeuken, Dr Darren Tomlinson (Biological Sciences), Professor Mark Wilcox, Dr Jonathan Sandoe, Dr Michael Messenger, Dr Andrew Kirby, Professor Robert West, Dr Bethany Shinkins (Medicine and Health), Professor Nikil Kapur, Professor Christoph Wälti (Engineering).

University and student support

Students raising awareness of the need to treat antibiotics with respect (Courtesy #seriouslyresistant).

On top of the research which academic staff carry out, the University community supports increased awareness of the need for control and proper use of antibiotics. Staff and students are being encouraged to pledge to become Antibiotic Guardiansby taking antibiotics as they are prescribed, taking steps to reduce the spread of germs and to challenge bad practice.

Students are also signing up to the #seriouslyresistant campaign which has similar aims.

Breadth of research excellence

In addition to the ongoing project to create the rapid diagnostic device, numerous researchers are working in related fields at Leeds, thanks to the University’s breadth of expertise.

The BAM complex studied by Professors Sheena Radford and Neil Ranson, left, and right, Professor Ranson with colleague Dr Rebecca Thompson supervising the installation of the University's cryo electron microscopes. 

• Professors Sheena Radford and Neil Ranson (Astbury Centre for Structural Molecular Biology) have used powerful cryo-electron microscopes and structural biology techniques to reveal new details about the operation of the BAM protein complex which facilitates the insertion of proteins into the outer membrane layer of bacteria containing, cells protecting them from attack by antibiotics. The new understanding will contribute to ongoing work to find new ways to kill resistant bacteria.
• Dr Jonathan Sandoe (Medicine and Health) has developed treatment guidelines for NHS doctors at Leeds Teaching Hospitals NHS Trust to improve the quality of antibiotic prescribing. This work explains the importance of making the correct diagnosis first time round, and includes advice on which type of investigations doctors should carry out help identify the cause of an infection. 
• Dr Alex O’Neill (Medicine and Health) is investigating the potential to review naturally occurring compounds with antibiotic properties, which have previously been dismissed as having potential for being developed for clinical use. Dr O’Neill says while a proportion of the 3,000 antibiotics discovered to date have been rejected as unsuitable, others may not have been rigorously evaluated as drug candidates. He has found a number of examples which have been re-tested over time and have been successful.
• Last year, Dr Liam Sharkey, (Biological Sciences) solved a 25-year-old question about how a family of proteins allowed bacteria to resist the effects of certain antibiotics. Proteins of the ABC-F family are a major source of antibiotic resistance in ‘superbugs’ but Dr Sharkey’s findings provided the first direct evidence of how this family of proteins ‘protect’ the bacterial ribosome, the protein makers in cells, from being blocked by antibiotics. 

The University of Leeds has committed to using its huge breadth of research capability to making a sustained focus on tackling the great global challenges of our time, of which anti-microbial resistance is one. Read more here about the University's commitment.

Further information

Journalists requiring more details or interviews with academic staff should contact Peter Le Riche in the University of Leeds press office on 0113 343 2049 or email p.leriche@leeds.ac.uk.

The lead picture above shows Dr Rebecca Thompson from the Faculty of Biological Sciences operating the University's cryo electron microscopes. This equipment will play a key role in studying protein operation to help researchers understand more about how bacteria become resistant to antibiotics.

The University of Leeds has pledged to support the Antibiotic Guardian campaign and ill we will champion or plan key promotional activities for World Antibiotic Awareness Week to the University community. The Antibiotic Guardian campaign is led by Public Health England.