ANTIBIOTICS

Intro: In 2014, the World Health Organisation (WHO) stated that antibiotic resistance was “happening right now in every region of the world” – leaving us at risk of entering a “post-antibiotic era”, where common infections could once again become fatal.

The WHO’s first global report on antibiotic resistance may sound alarmist, but it reflects the crucial role antibiotics have played in treating microbial diseases and infections since first becoming available in the 1930s.

Antibiotics were discovered in 1928 by the Scottish bacteriologist Alexander Fleming while he was working at the St Mary’s Hospital Medical School in London. During the First World War he had served as a medic in military hospitals behind the Western Front, where he witnessed the death of many soldiers from wounds that had become septic as a consequence of bacterial infections. After the war, Fleming directed his research efforts towards finding better ways of dealing with such infections and, according to his later account, discovered penicillin through chance and luck. A fungal mould of the genus Penicillium had infected a Petri dish containing a bacterial culture, after the spores had apparently blown into Fleming’s laboratory through a window that had accidentally been left open. As he was about to throw the Petri dish away, Fleming noticed that the bacteria around the mould had been killed, leading him to isolate the active substance produced by the mould, which he named penicillin.

A Medical Revolution

It took ten years for any serious work to start on developing penicillin into a usable antibiotic and, in the meantime, the German pharmaceutical company Bayer developed the sulphonamide antibacterial drugs, sold under the name of Prontosil. The beginning of the Second World War led to renewed interest in penicillin, and a team at Oxford University – led by Howard Florey and including the Jewish, German-born Ernst Chain, who had fled Germany in 1933 to escape persecution – developed a method of producing penicillin for medicinal use. For this work they, together with Fleming, were later awarded the Nobel Prize for medicine.

Making enough penicillin for armies during the Second World War proved difficult until deep fermentation was developed in America, coming just in time to provide sufficient supplies for the armed forces during the invasion of Normandy in June 1944. After the war, further research improved penicillin, and other antibiotics were developed, leading to a medical revolution that, coupled with the widespread use of vaccines, has dramatically reduced the impact of fatal or debilitating diseases and infections.

Growing Resistance

Almost as soon as he began to work on penicillin, Alexander Fleming recognised the potential for bacteria to develop resistance, because of the capacity such microbes have to replicate very rapidly, providing the opportunity for evolution to occur. Should a mutation arise which confers resistance, it can spread quickly – facilitated by the further use of antibiotics, because these would then wipe out any non-resistant bacteria that would otherwise compete with the resistant strain. Despite repeated warnings by Fleming and many others not to misuse antibiotics, it quickly became common practice for doctors to prescribe them for a much wider range of illnesses than they should have, often simply because patients demanded them.

Today, antibiotics are still being given to patients who have colds or flu – viral infections against which such treatments are ineffective – and are also widely used in veterinary medicine as a preventative measure in livestock farming rather than as a treatment for a specific disease. In some countries, antibiotics are also used as growth promoters in livestock, it having been found that animals treated in this way often perform better. About two-thirds of all antibiotics are now used on farms, and while these are different from the ones used to treat people, such use can nevertheless result in a build-up of resistance, which has the potential through genetic mutation to transfer to medicinal human antibiotics.

Resistance will build up in bacteria even where antibiotics are used responsibly, but the more they are used, the quicker this will happen, so it is vitally important that they are not overprescribed or misused in livestock farming. Unfortunately, this advice has not always been followed, leading to a number of infectious diseases becoming increasingly difficult to treat. Some of the best-known examples are those particularly associated with hospitals, known by most people as “superbugs”, such as MRSA (methicillin-resistant Staphylococcus aureus). These bacteria are not necessarily any more virulent than strains that remain sensitive to antibiotics – the problem being that they are much more difficult to treat, particularly those which have become what is known as multidrug-resistance. Stricter regimes of hygiene in hospitals have been found to minimise the spread of MRSA, but it nevertheless represents a serious and ongoing problem for healthcare.

Multidrug-resistant Mycobacterium tuberculosis is another microbe becoming more common worldwide. As its name suggests, this bacterium is responsible for tuberculosis, a potentially fatal infectious disease of the respiratory system, which was thought to be under control through the use of antibiotics until the 1980s, when resistant strains began to emerge. Today, more than 100,000 people are thought to die every year as a consequence of this resistance – many of whom live on the African continent, where treatment may not be available and where, in some cases, those infected already have an immune system weakened by HIV.

Developing Solutions

One potential solution to antibiotic resistance would be the regular introduction of new classes of antibiotics to which pathogens have no resistance, but so far this has not happened. Big pharmaceutical companies, responsible for the design and introduction of most new drugs, have been reluctant to invest in developing new antibiotics because it is difficult and expensive, and antibiotics are not very lucrative compared to other classes of drugs. Patients usually only need antibiotics for about a week, and new ones would only remain effective for as long as it took for resistance to build up, which can take just a few years. Drugs for conditions such as heart disease, for example, are often used for long-term treatments so, once pharmaceutical companies have made the initial investment involved in development and clinical trials, they can expect to sell successful drugs for a much longer period.

In its 2014 report, the WHO identified serious gaps in available information on the types of antibiotic resistance occurring globally, which, together with a lack of coordination between countries, was impeding possible responses to what has become a serious problem. As well as stating that increased information gathering, and sharing is needed, the report recommended greater government investment in research, and the responsible use of antibiotics in medicine and agriculture. Everybody has a part to play, though, from doctors not overprescribing antibiotics to patients using them exactly as prescribed.

Alternative Theories

In January 2015, researchers at Northeastern University in Boston, Massachusetts, reported that they had discovered a new antibiotic named teixobactin, which they had isolated from the soil bacterium Eleftheria terrae through a new culturing method. It was the first new class of antibiotic to be found for almost 30 years, and in tests proved effective against a range of bacteria, including MRSA and Mycobacterium tuberculosis, neither of which appeared to develop resistance to it. Teixobactin works by inhibiting the production of those fats that form a constituent part of cell walls and preventing bacteria from growing, while most other antibiotics target proteins in the cell wall or inside the cell to kill fully grown bacteria. The research team thought that E. terrae might have developed this function in response to naturally occurring resistance.

If they are correct, resistance to teixobactin is less likely to develop in the first place and, even if it does, will take much longer to build up than resistance against existing antibiotics. Clinical trials should take about five years and, if it passes, the research team predicts that teixobactin could remain effective for over 30 years. Even if teixobactin fails these trials, this new method of culturing soil bacteria in the laboratory can be used to investigate the potential of many other species of bacteria to produce antibiotics. This on its own could lead to a whole new era in the fight against antibiotic resistance.