The hunt for new antibiotics
Hardly a week goes by without a report of someone dying because of an infection from an antibiotic-resistant superbug. Amid mounting fears of a “post-antibiotic” age, scientists are pursuing a variety of innovative routes in the quest for new treatments.
Kate Elliot, Senior Ethical Researcher, Rathbone Greenbank Investments
In 1928 an untidy researcher studying influenza in a London hospital accidentally left a Petri dish contaminated with Staphylococcus lying in the corner of his laboratory. He then went on holiday for two weeks. On his return, Alexander Fleming found that a fungus had formed on the bacteria, preventing its growth. Penicillin was born.
Fleming was not the first to understand the antibacterial qualities of mould. The ancient Egyptians had already applied mouldy bread to wounds. But this particular mould, when grown in a pure culture, was found to be especially potent, killing a number of disease-causing bacteria.
Other scientists carried on Fleming’s initial work, and by 1945 penicillin was available for general use. Just a year later Fleming himself was warning of the dangers of overusing antibiotics. “The thoughtless person playing with penicillin treatment is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism,” he told readers of the New York Times. “I hope the evil can be averted.”
It seems that the temptation to resort to antibiotics has been too great. The most recent figures show that Britons consumed over 491 tonnes of antibiotics in 2017. Animals — livestock, horses and pets — consumed another 282 tonnes.
Inevitably, antibiotic resistance is increasing. With no new antibiotics discovered in 30 years, the World Health Organisation (WHO) says we are facing a serious global threat.
The WHO’s worries are especially focused on the emergence of so-called superbugs, such as methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile (C. diff), which are extraordinarily difficult to kill. These superbugs are already responsible for 700,000 deaths a year, and a 2014 study — led by economist Dr Jim O’Neill and produced for David Cameron — warned that they could kill more people than cancer by 2050, at a cost of £63 trillion to the global economy.
In January this year it was reported that genes associated with antibiotic superbugs have been discovered in water in the High Arctic. Researchers were justifiably puzzled, since there is so little human activity in that part of the world and the superbug genes matched ones first identified in Delhi. Scientists now believe that the genes were carried north by migrating birds that picked them up in surface water contaminated by sewage in India.
“We cannot tackle the rise of antimicrobial resistance without focusing on water, sanitation, hygiene and infection prevention control,” says Helen Hamilton, a senior policy analyst at WaterAid. “In today’s globalised world, a drug-resistant infection in one part of the world will not be constrained by national borders.”
Searching for cures
With the scale of the problem now beyond question, a number of entirely new methods for curing bacterial infections are being explored. Two in particular, phage therapy and phytochemicals, show promise.
Bacteriophages, known as phages for short, are a type of virus that infects a bacteria cell. The phage inserts its DNA into the bacteria and creates proteins that kill them by making holes in the cell wall from the inside out. Phages are very specific in the bacteria they attack, so that the naturally occurring good bacteria are unaffected, which means that they do not cause the stomach problems associated with antibiotics.
Phytochemicals are plant-derived compounds that have a pharmaceutical action. They are present in certain fruits, grains and vegetables. The most common are antioxidants, which have been associated with reducing the risk of cancer. Scientists are now hunting for phytochemicals with antibiotic properties.
Meanwhile, Vedanta Biosciences, based in Cambridge, Massachusetts, is trying another approach — enhancing the microbiome, the vast army of microbes in your body that protects you from disease and breaks down your food. By collecting healthy samples from people around the world, mixing them together and delivering them in pill form, Vedanta hopes to build a stronger immune response in microbiomes weakened by overexposure to antibiotics.
University of Colorado Boulder researchers working on developing quantum dots -— tiny crystals of semiconductors that could harness solar energy to make fuel — knew the technology had already been used for imaging in cancer research. By teaming up with colleagues developing new antibiotics, they have developed a novel type of quantum dot that can selectively target bacteria.
The dots are tiny. As researcher Prashant Nagpal says: “A quantum dot is to the width of a hair roughly what a city block is to the Earth.” The hope is that the dots can be placed in a patient’s body and then be activated using a targeted light source to clear infections in specific places. The dots would be very cheap to produce, and — at least theoretically — they would require a dose one million times less than traditional drugs.
In another example of repurposing existing technology, a star-shaped polymer developed 15 years ago to add viscosity to automotive paints and engine oils was found to have the capability to deliver anti-cancer drugs. Then scientists at the University of Melbourne found that a version of the polymer, called SNAPP (Structurally Nanoengineered Antimicrobial Peptide Polymers), was toxic to bacteria.
Exploring unusual avenues
The pharmaceutical industry was almost exclusively focused on antibiotics in the wake of the Second World War, but scientists have now devoted more than half a century to building on the molecular scaffolds erected during that era. The point of diminishing returns has long since been reached. Now much of the industry has moved on to less frustrating challenges.
“You might be able to squeeze one or two compounds out of these classic scaffolds, but they just don’t have much more to give,” says Eric Gordon, co-founder and chief scientific officer of US-based Arixa, which is developing novel resistance-defeating compounds that can be administered alongside antibiotics. “Most people think that with a big cash infusion we would be sailing along again, making antibiotics. But the fact is that nobody knows how to make them anymore.”
It is this worrying reality that is compelling researchers to explore ever more unusual avenues. Scientists at Oregon State University, for instance, are investigating whether an answer might lie in the layer of mucus that coats the outer surface of young fish.
Their interest stems from the fact that this mucus helps protect fish from harmful bacteria, fungi and viruses. “We believe the microbes in the mucus add chemistry to the antiseptic power of the mucus and that new bioactive compounds might be discovered from the fish microbiome,” says Dr Sandra Loesgen, head of the research group.
Perhaps the most unusual search of all is being carried out by an international group of medieval historians, microbiologists, medicinal chemists, parasitologists, pharmacists and data scientists. Known as the AncientBiotics team, they are combing ancient texts for medieval medicines of the past. A 1,000-year-old Anglo-Saxon eye-salve recipe, which contains a mix of wine, garlic, allium and ox gall left to ferment for nine nights, has been found to kill MRSA in mice.
Work of this kind is not without precedent. Chemist Tu Youyou, who was awarded the Nobel Prize in Physiology or Medicine in 2015, searched more than 2,000 herbal treatments from ancient Chinese literature before discovering a new malaria therapy. It could well be that the most effective cures of the future lie in the past.
Wherever they might be found, the race to find answers is becoming increasingly urgent. The greatest fear is that bacteria have become so adept at cultivating resistance that this is a fight that we can prolong but never win. “We risk living in a post-antibiotic era,” says Floyd Romesberg, a researcher in natural antibiotics at California-based Scripps Research. “We’re buying time. You just have to keep running as fast as you can to stay in place.”
Fields of innovation
The overuse of antibiotics in farming is a key part of the problem. Richard Pearson, a specialist pig vet based in Wiltshire, discovered a simple way of helping farmers to eliminate enzootic pneumonia from their herds and reduce the use of antibiotics. Instead of dosing newborn piglets with a protective antibiotic, farmers dosed the mothers. Mr Pearson explains: “In effect, this targeted treatment of 4,000 sows removed the need to treat the 100,000 pigs they produce annually.”
Another approach is championed by the #ColostrumIsGold campaign, which is run by the Responsible Use of Medicines in Agriculture Alliance (RUMA). It involves ensuring that baby animals receive sufficient amounts of their mothers’ milk soon after they are born. Just after birth, the so-called first milk — or colostrum — of cows, sheep and pigs is full of antibodies, energy and essential nutrients. Delivering it at the right time can eliminate watery mouth E. coli infection in lambs and halve the cases of pneumonia in calves.