Across the world, there is a growing problem with antibiotics — there have been years of misuse by patients, doctors and even farmers seeking greater yields from livestock, with the result that microbes have learned to live with these once potent drugs.
Ramanan Laxminarayan, formerly of the Public Health Foundation of India and now director of the Center for Disease Dynamics, Economics and Policy in Washington DC, has highlighted how the greatest burden of resistant disease falls on low and middle-income countries. India, in particular, has an issue with antibiotic use, surpassing even China for the highest number of sales in 2014. Growing economic success may give India the dubious privilege of achieving not just the highest use in humans, but also in animals — in 2030 India is predicted to be the greatest user of antibiotics in livestock.
Clearly, one solution to this global crisis would simply be to use fewer doses of antibiotics, to help preserve them for the most serious infections. However, without a long campaign of education and the watertight enforcement of bans on inappropriate antibiotic use, this approach is doomed to failure. Can we develop new antibiotics quickly enough to overcome the rise of resistance?
Again, this approach may be destined to fail because microbes have been fighting each other with natural antibiotics for billions of years and somewhere in nature there probably already exists an answer to drugs that kill microbes, or slow down their rate of growth. Worryingly, many microorganisms have the ability to cooperate to build structures called bio-films that provide physical protection from drugs; bugs in bio-films live in sufficient proximity to each other to allow the exchange of the pieces of genetic information required for resistance. Resistance, then, seems an almost insurmountable problem.
Given such issues, many scientists are now looking for an alternative route to protection against microbes. Simply separating people and bugs has always been an effective strategy — washing hands is one of the most valuable lessons taught to young children, and campaigns such as SuperAmma have seen significant changes in behaviour that should lower the burden of disease.
Can we find other ways of separating ourselves from microbes that would be useful in preventing the infections of skin wounds such as burns, lowering the numbers of dangerous bacteria that we carry in our noses and throats (such as the bacteria that cause a form of meningitis or pneumonia) or that can protect our eyes from devastating fungal infections? Even better, can we do this without causing the microbes to fight back with drug-killing resistance?
The approach that we have taken at the University of Sheffield came originally from a study of how our cells stick together to form tissues such as skin. There are structures on the surfaces of cells that resemble Velcro — highly organised patches of adhesive molecules that enable cells to cling tightly together. In some cases, these are long-lasting and static, providing leak-proof seals around blood vessels. In other cases they are shortlived and dynamic, allowing mobility, for instance when our white blood cells are travelling through tissues to get to the site of an infection.
We discovered that some types of bacteria and yeasts can “hijack” the dynamic sites, to allow them to stick to our tissues even when our defences try to dislodge them with mucus, tears or rapidly-flowing blood. This is the starting point of an infection, when a colony of microorganisms attaches and starts to grow, often penetrating deeper into tissues to cause serious disease. Even superficial infections can cause problems, by preventing the healing of bed-sores and ulcers in the elderly, for example. Different types of microbes use different types of human molecules to cling to and targeting all of them would be very expensive. Our approach is not to target the molecular hooks themselves but the material in which they are held to form the sticky patches. On Velcro, hooks are embedded in a base layer of woven material but on our cells this is formed by a sort of molecular raft called a microdomain.
We have discovered how to weaken one type of microdomain, in a way that is analagous to stretching Velcro, pulling the molecular hooks further apart and significantly lowering the stickiness of the patches on cells. By addressing only one type of microdomain, we have found that we do not affect the normal behaviour of our cells, but we do make bacteria and fungi much easier to wash away.
In a sophisticated three-dimensional model of human skin, we lowered the burden of a common hospital-acquired infection (Staphylococcus aureus, otherwise known as MRSA) using a cheap and simple application of natural protein fragments called peptides. These peptides did not prevent wound-healing in the skin and, importantly, they did not affect the growth of the bacteria. In the absence of a direct action on the bugs themselves, resistance cannot spread through a population and so the peptides should be an effective, long-term treatment for infections.
Our more recent work has also shown that combinations of peptides and conventional antibiotics are able to prevent infections, even when using drug-resistant bacteria such as MRSA. We believe that combinations of new and old approaches may be an important way of fighting infections in the future, giving new life to existing antibiotics and extending the life spans of new ones when they reach the clinic.
The writer is professor of immunology, University of Sheffield, UK