David Cox :Off the coast of California, nearly 20,000 feet below the surface of the Pacific Ocean, scientists from the San Diego Institute of Oceaneography are collecting samples of marine life from the ocean floor. At first glance, these small clumps of sediment may appear nothing special, but the micro-organisms which lie within may one day provide an answer to one of the most urgent issues in modern healthcare: the global antibiotic resistance pandemic.To put the scale of the problem in perspective: the Ebola epidemic in West Africa captured the headlines in 2014, and in total the virus accounted for just over 11,000 fatalities, making it as the most devastating outbreak of the virus in history. Current estimates place the annual number of deaths from antibiotic resistant bacteria at around 700,000 worldwide. Unless things change this figure is predicted to rise to 10 million by 2050, with growing numbers of bacteria already fully resistant to every clinical antibiotic available.Speaking at the recent Uppsala Health Summit, Professor Otto Cars described resistance to antibiotics as “a silent tsunami, crumbling down the pillars upon which modern medicine is built.” Cars, who has spent decades campaigning for awareness on the topic, describes the problem as one of complacency. While antibiotic consumption has increased by 36% in the past decade, no new classes of these drugs have been discovered since the 1980s.In June, the World Health Organisation unveiled a global action plan to tackle antibiotic resistance. One of the stated aims is to have a whole new class of antibiotics in development by 2019.But is this really feasible? To understand the challenges, it’s necessary to look at how bacteria become resistant in the first place.”The most common way this happens is through the acquisition of genes from other resistant bacteria,” says Gerry Wright, a chemical biologist at McMaster University in Ontario, Canada. “Bacteria are very promiscuous and the most shocking thing we’ve realised over the past 60 years is just how rapidly this gene sharing occurs. They often acquire these resistance genes in packages, giving them resistance to multiple antibiotics at the same time, and that’s a major problem in hospitals. Resistance also develops through chance mutations during DNA copying when bacteria reproduce. This is believed to be how bacteria became resistant to rifampin, a drug used to treat tuberculosis.”At the molecular level, such mutations can prevent an antibiotic entering the bacteria cell at all, altering the target molecules so that they don’t bind to the antibiotic anymore, or enhancing the efficiency of efflux mechanisms within the bacteria which allow it to simply pump a drug back out again. Certain genes, if acquired, can actively degrade antibiotics, limiting their effectiveness once they’ve entered the cell.In order to discover brand new medicines capable of destroying these mutant bacteria, many scientists are turning back to nature. At the University College London School of Pharmacy, Simon Gibbons is looking at the chemical compounds which give certain plants their antiseptic properties.”Instead of just focusing on killing resistant bacteria, we’re also looking at ways of altering them to make them susceptible again,” he says. “We have a couple of projects looking at chemicals which can inhibit antibiotic efflux in bacteria, and other molecules which can inhibit the transfer of plasmids. Plasmids are small DNA molecules which spread antibiotic resistant genes between bacteria.”Gibbons is monitoring a clinical trial looking at a compound found in bearberries. This chemical is used to treat cystitis, an infection caused by E.coli bacteria, by either killing them or preventing them binding to the urinary tract. Scientists are interested in whether it is just as effective at dealing with other microbes.However, not everyone is convinced that plants are the most likely source of compounds capable of dealing with the world’s most virulent bacteria. “We don’t have many plant-derived anti-bacterial agents because of the evolution scale,” says Richard Lee, a researcher at St. Jude Children’s Research Hospital in Memphis. “Plants evolve slowly while bacteria are the exact opposite, so plants tend to use non-specific approaches to combat bacteria which are harder to translate into human therapeutics.”Over the past 80 years, the main focal point of the search for new antibiotics has been soil microbes, and the variety of substances they produce to kill each other as part of their ongoing chemical warfare. But until recently, we haven’t been especially adept at keeping them alive in the lab for long enough to obtain their weapons for our own use.Last year, scientists in the US and Germany developed a novel method which led to the discovery of a substance called teixobactin, which they believe has the potential to become the first new antibiotic since 1987. Teixobactin has the ability to destroy some of the most dangerous drug-resistant bacteria, such as MRSA, and has a very low potential for the development of resistance – but it is ineffective against the most hard-to-treat family of all: gram-negative bacteria. These bacteria develop resistance exceptionally quickly due to their rapid DNA sharing, which has seen them evolve an extra protective cell membrane and sophisticated efflux.To target them, scientists are turning to life in some of the most far-flung corners of the planet. Organisms living thousands of feet beneath the ocean surface have evolved their own unique ways of defending themselves against microbes over millions of years, most of which are still unknown. A compound called anthracimycin, produced by a particular bacterium living in the depths of the Pacific, has demonstrated potential but discovering such compounds is just a small part of the challenge. The biggest problem is finding those which aren’t toxic to humans. “Bacteria, humans and all living creatures, share the same biochemical mechanisms that are essential to life,” Wright says. “But these are typically the things that antibiotics target. One way to kill a bacterium is to punch a hole in its membrane, but you need to find something that selectively punches holes in bacteria and not human cells.”Gibbons feels the WHO’s 2019 deadline is unrealistic. “There’s a lot of work from simple testing to safety testing, and then animal models involving mice or rabbits, before you even think about a clinical trial. And you have to prove that you can generate enough of the substance itself. So I doubt we’ll see any new classes of antibiotics until 2021 or 2022 at the very least.”Due to such difficulties, others are instead looking at redesigning old, discarded antibiotics to increase their stability and effectiveness. Some were originally abandoned because they only worked on a small handful of bacteria, but now it’s thought that a range of more narrow spectrum treatments may be a better way to avoid driving resistance.Lee is currently researching spectinomycin, an antibiotic introduced in the 1960s to treat gonorrhoea, before being cast aside as it only worked in massive doses. He believes that a remodelled version has the potential to work well against a range of respiratory tract infections and sexually transmitted diseases.”The drug has always been very safe, and fifty years on we now know its crystal structure,” he says. “So we can exploit that along with all the old knowledge from the pharmaceutical companies who tried to develop it in the 1980s, to improve its design and help it access the target bacteria more effectively.”Of course, some bacteria will eventually become resistant to spectinomycin and other old antibiotics, but Lee believes that it is possible to design these drugs so this comes at an evolutionary cost to the bacteria.”Because of how they work, some antibiotics are just harder for bacteria to develop resistance against,” he says. “And while mutated bacteria may be able to evade the drug, they may not be able to survive as well and for as long. So you could become infected but it won’t be as virulent and threatening.”But developing a new product from scratch or even rewiring an old one comes with substantial costs and challenges, and so there are many scientists focusing exclusively on ways to make our existing antibiotics useful once more against resistant bacteria. One popular idea is combination therapy – combining multiple drugs together to form a cocktail mix which is both more potent and difficult to evade.”Over the past decade we’ve found that specific genes essential for the life of the bacterium, interact with multiple other genes in the cell in a complex web-like fashion, much like pages on the internet,” Wright says. “So our idea was, if we combine antibiotics with other molecules and use those combinations to target this web in various random fashions, perhaps we can unexpectedly improve antibiotic activity or overcome bacterial resistance in new ways?”Such random screening required vast numbers of drug combinations to be tried and tested, a thankless needle-in-a-haystack task which would have taken years of labour in decades gone by. But with 21st century robotics technology, Wright and his colleague Eric Brown are able to screen thousands in a mere afternoon.There can still be unexpected drawbacks as it is often hard to match the exposure of two drugs at the site of infection to see the desired effect.. Wright and Brown thought they’d struck gold with a combination of the antibiotic tetracycline with a drug called imodium, used to treat diarrhoea. Imodium enhanced tetracycline’s ability to penetrate bacteria, but further testing showed this only worked in the gut, limiting its usefulness.”The alternative is to have one drug that simultaneously hits several , often related bacterial targets making resistance harder to develop,” Lee says. “This is a serendipitous strategy applied by many currently successful antibacterial agents including fluoroquinolones and beta-lactam antibiotics. But from a de novo discovery angle this is technically much harder to do.”As a result, some feel the right combinations of drugs have major advantages when it comes to developing viable products. Given that the individual drugs themselves are known to be safe, and can be produced in large quantities at a reasonable cost, the path from lab to clinic should, in theory, be much faster and less expensive.Wright believes combination therapy is the main way forward, just as combinations of antiviral drugs proved to be the way to control HIV. “With multiple molecules, bacteria often have to develop resistance to each one. And with three or even four molecules together, there’s less and less chance of this actually happening.”- The Guardian
