Antibiotic use underpins much of modern medicine and has saved lives that might otherwise be lost to very common infections and minor injuries. According to the World Health Organisation (WHO), antibiotics and vaccines add an average of 20 years to our lives. Advanced therapies such as cancer treatment and organ transplants, which make patients particularly vulnerable to infection, depend upon the use of antibiotics.
We are in an arms race with bacteria, which naturally develop resistance to the antibiotics we use against them, becoming ‘superbugs’. The 1950s and 60s were golden years, when new antibiotics were developed faster than the bacteria could develop resistance. Since then, the pipeline for new drugs has dried up. No new classes of antibiotics have been developed since the 1980s, and research on treatments to replace antibiotics is still in the early stages.
The WHO’s Antimicrobial resistance: global report on surveillance 2014 paints a chilling picture - very high rates of resistance have been found in all WHO member countries for common diseases. Patients who contract these disease-resistant strains are at risk, and their treatment costs more. Drug-resistant infections in the EU add at least €1.5 billion each year.
The good news is that researchers are taking on the challenge of antibiotic resistance, many of whom use STFC-funded facilities. At the Diamond Light Source, a group from the Universities of East Anglia and St Andrews recently studied ‘Superdrug’ bacteria in extreme detail. They pinpointed the structure of a protein responsible for creating the ‘camouflage’ that allows Gram-negative bacteria (which cause a range of illnesses, including E-coli, salmonella and meningitis) to hide from the body’s defence mechanisms as well as offering protection against antibiotics. Group leader Prof Changjiang Dong, from UEA’s Norwich Medical School, said “Many current antibiotics are becoming useless, causing hundreds of thousands of deaths each year. The number of superbugs is increasing at an unexpected rate. This research provides the platform for urgently-needed new generation drugs”.
In 2011, Dr Jon Marles-Wright was part of a group of scientists from Newcastle University and the Nara Institute of Science and Technology in Japan that used Diamond to identify a group of proteins that enable certain bacteria to build effective cell walls. Again, these proteins may provide a novel antibiotic target for a range of bacteria. Dr Marles-Wright said that “This discovery provides us with a highly attractive new target for drug discovery programmes”.
Medical Research Council (MRC) scientists from the Research Complex at Harwell used crystallography at Diamond to uncover the structure of NDM-1, a vicious form of bacterial enzyme that is resistant to even the most powerful antibiotics. Producing a model of bacteria such as NDM-1 enables researchers and pharmaceutical companies to develop new treatments. Professor Sharon Peacock, a member of the Medical Research Council Infections and Immunity Board, said “Identifying the structure of NDM-1 is a crucial step towards ensuring that drug development is based on a sound understanding of the mechanisms of bacterial resistance to antibiotics”.
A collaboration of scientists has used the Diamond Light Source and the European Synchrotron Radiation Facility (ESRF) to understand the 3D structure produced when penicillin binds to a common disease-causing bacterium. Knowing how drugs work is an important step in improving them so that they can overcome resistance. In 2012, scientists from GlaxoSmithKline used ESRF to visualise how a new type of antibiotic can kill bacteria that have proved resistant to other treatment.
Light sources aren’t the only facilities that can be used for antibiotic research. In 2011, funding from the Engineering and Physical Sciences Research Council allowed scientists from Kings College, London to use ISIS to investigate the antibiotic Amphotericin, which has been the first line of defence against fungal infections since the 1950s. Emerging resistance to Amphotericin poses serious problems for AIDS and chemotherapy patients, but until we learn more about how it works, finding a replacement drug will be difficult.
In 2013, a collaboration of scientists from Queen Mary University of London, ISIS, The University of Toronto, The University of Szeged and Beijing Normal University used neutrons to study how penicillin goes from completely inactive to specifically active in the presence of target bacteria. Building on the successes emerging from the penicillin project, new and exciting neutron and muon beam experiments are on-going, with experiments being designed for other bioactive molecules.
In a long-standing project, scientists from ISIS, Newcastle University and the Bragg Institute in Australia have been working to mimic the defence system of gram negative bacteria, such as E coli. The result is a functioning model of the bacterial outer membrane, which will serve as an important tool in the development of new antibiotics. The team used neutrons at ISIS to determine the nanoscale structure of the model membrane, and they are now able to undertake realistic experiments since the model recreates conditions in live bacteria more closely than ever before.
Developing new antibiotics is only one of the strategies needed to tackle the issue of resistance. All across the world, patients are taking antibiotics unnecessarily, failing to complete courses of antibiotics, taking sub-standard drugs and sharing their antibiotics with others – all of which can spread antibiotic resistance. In farming, the widespread use of antibiotics to promote growth is adding to the problem. Our use and misuse of antibiotics is driving the rise in resistance. The focus of the Longitude Prize (chosen by the public) is to encourage the development of a cheap, accurate, rapid and easy-to-use point of care test kit that will allow more targeted use of antibiotics, and a reduction in misdiagnosis and prescription.
With science, care and concerted effort, we can turn the tide against bacteria once more, and continue to enjoy the benefits of modern medicine in the future.