Low profit margins and the difficulty of finding new drugs has led to big pharma shutting down its antibiotics programmes. But now researchers are adopting new approaches to tackle drug-resistant superbugs
Matt Cooper, a medical chemist at the University of Queensland, Australia, puffs out his cheeks and scratches his head. He’s trying to explain why the pipeline for new antibiotics is quite so dry. “The problem,” he says, “is that finding new antibiotics is now really, really hard.”
It’s a worrying concession given how badly we need new drugs. Drug-resistant superbugs already kill hundreds of thousands of people every year and, according to the Antimicrobial Review (AMR) committee chaired by Jim O’Neill (see box), if left unchecked they will kill 10 million of us every year by 2050. That’s more than will be killed by cancer, diarrhoeal disease or road traffic accidents.
One of the reasons drug discovery is so hard, Cooper says, is that it has suffered underinvestment since the late 70s. Big pharma companies, the traditional engine room for drug discovery, started to drop their antibiotics programmes, focusing instead on more profitable drugs that are sold at a higher price and taken for the rest of a patient’s lifetime, such as those for diabetes, cancer and heart disease. The cholesterol-busting drug Lipitor, for instance, at its height raked in a cork-popping $13bn (£8.4bn) a year for pharma giant Pfizer. Antibiotics, cheaper per pill and taken for about a week, could not compete.
Another reason behind the exodus of big pharma was that finding new drugs became difficult. “We took most of the low-hanging fruit in the golden era of antibiotics in the 50s to the 70s,” Cooper says. Most antibiotics came from compounds made by micro-organisms in the soil. Scientists, like children at the beach, needed only a bucket and a spade to collect soil samples, bring them back to the laboratory to be cultured, and try to identify any compounds that could kill bugs. “We were finding 12 antibiotics a year. Nobody worried much about resistance or overuse because we thought there would always be more.”
Scientists have since scoured ocean beds and deep caves for micro-organisms that make new compounds but had come up empty-handed – until, that is, earlier this year when a team from Northeastern University in Boston, US, announced they had discovered 25 potential new compounds in the soil. One of them, teixobactin, showed promise in laboratory tests against otherwise drug-resistant strains of tuberculosis and the hospital superbug MRSA (methicillin-resistant Staphylococcus aureus). Teixobactin is not active against the harder-to-treat type of bacteria called gram-negative bacteria, but its announcement caused much excitement. If approved, as is hoped within the next five years, it will be the first new class of antibiotic developed since 1987.
The researchers used a technology called iChip, currently under exclusive licence to US company NovoBiotic Pharmaceuticals, to tap into the much-prophesied microbial “dark matter” – the roughly 99% of micro-organisms that cannot be cultured in laboratory conditions and were thus unseen by the early antibiotic discoverers. iChip allows the microbes to be cultured while still in the soil. “The rule of thumb is that you need 50 promising leads for one drug,” says Kim Lewis, the director of Northeastern University’s Antimicrobial Discovery Centre who led the research team, “so we’re not expecting much else from these 25 candidates, but we will keep searching for more.”
Cooper, too, is on the hunt, but through a different type of fertile ground. In March this year, he launched the Community for Open Antimicrobial Drug Discovery, a nonprofit initiative that aims to pool together the many thousands of chemicals made by academic chemists and screen them for potential antibiotic use. “We have seed banks and tissue banks, so why not have a chemical bank?” he says. “Maybe the answer has been in front of us all this time, but until we start hunting through every shelf in every laboratory around the world – not just those that have been trying to come up with antibiotics – we will never know.”
Speak with any antibiotics researcher for long enough about finding a new antibiotic class and they will definitely use the words “holy grail”; it’s a nod to how wondrous such an event would be, but it’s also a concession that, even at the most optimistic timelines, it is beyond the reach of today’s jobbing doctors, who need it most.
A more immediate solution is to try to eke out the life of existing antibiotics. Resistance breakers, such as HT61, which is in development by UK biotech company Helperby, aim to do just that. “We think it works by punching holes in the membrane of bacteria, which allows the old antibiotics to fly though into the inside and be active in high concentration,” says Anthony Coates, chief scientific officer at Helperby and a medical microbiologist at St George’s, University of London.
HT61 can help to resuscitate some antibiotics against drug-resistant bacteria such as MRSA and could be available within two to four years. It can’t be ingested, but can, for example, be applied pre-emptively around the inside of a patient’s nose to reduce the risk of a serious infection.
Further back on the developmental pathway, a handful of biotechs are developing other resistance breakers, some of which might be able to be given orally or intravenously with an antibiotic. “We’ll need about five or six different types,” Coates says, “each of which are able to resuscitate a range of different antibiotics, if we’re to have a reasonable chance of carrying on with modern medicine.”
He’s wary that such efforts will be only a stopgap and that five or six other resistance breakers will be needed for when bacteria inevitably develop resistance. It’s a concern that worries David Livermore, too. “Finding a single new wonder antibiotic isn’t enough,” says the medical microbiologist at the University of East Anglia and former director of the government’s Antibiotic Resistance Monitoring Laboratory. “Bacteria will find a way around it. What matters is either engineering a flow of new compounds or changing the nature of antimicrobial treatment in such a way that we select much less resistance than we have in the past.”
One option is to use so-called non-antibiotic approaches. A fairly left-field approach is to make drugs that do not kill the bacteria – and thus do not induce resistance – but instead stop them from becoming harmful. Bacteria, like football fans, are harmless on their own and become bothersome only when in large groups. When in a sufficiently large crowd they secrete molecules called virulence factors, which cause disease. Some researchers are testing compounds that can interfere with quorum sensing, the process bacteria use for communicating with each other, so that the bacteria go on thinking that they are alone and do not secrete the disease-causing factors. Others are attempting to starve bacteria of the metals they need to survive.
Although these approaches show promise in petri dishes, Livermore says, they are a long way from being any immediate help. “There’s often a disconnect between very good scientists with elegant ideas and the generality of day-to-day clinical practice.”
For Livermore, the biggest need is to develop technologies that can let doctors rapidly diagnose resistant infections and treat them accordingly. “This way, doctors can avoid using broad-spectrum antibiotics, which are a bit like doing carpet bombing in the second world war,” he says. “It’s incredibly wasteful. You drop lots of bombs around the target on the reckoning that you’ll hit it and never mind what damage you also do.”
The damage of such flippant use of antibiotics is that it can select for drug-resistant strains by wiping out the good bacteria in a patient’s gut, allowing other troublesome bugs such as Clostridium difficile to colonise. If a doctor knew exactly what type of bug – and resistance mechanism – they were dealing with they could tailor treatment accordingly. Technologies are available that can read the entire genome of a bacterial sample in a few hours, but they are not ready for clinical use: they are too expensive, costing a few hundred to a thousand pounds per sample, and are not yet reliable enough to detect every possible resistance-specifying mutation.
“These are big challenges in the development of these technologies,” Livermore says, “but I’m convinced they’ll come through gradually.” Another boon for this approach, he says, is that if and when such rapid diagnosis becomes commonplace, it can complete the loop and pull back in the pharma companies that abandoned drug discovery by making it easier for them to find the right patients for clinical trials.
“Clinical trials of antibiotics are extraordinarily expensive,” he says. Trials can cost between £60m and £100m, and when you account for the fact that only a few of the thousand or so patients you recruit have the drug-resistant bacteria that you want to test your drug against, it can end up costing around £1m per relevant patient. “The size and cost of these trials is a huge financial disincentive for big drug companies and a huge barrier to small ones.”
With reliable, rapid-diagnostic techniques, companies will be able to recruit only the relevant patients and do smaller, cheaper trials. “We need to get a lot smarter to make these trials more doable by smaller biotech companies,” Livermore says, “rather than have this chicane in development where small companies have to partner with big pharma, which has… a lack of great enthusiasm for antibiotic development.”
Money matters are also on Cooper’s mind: “We also need to think long and hard about the antibiotic drug pricing and whether it’s ethically acceptable to pay so much for life-extending drugs but still expect to pay peanuts for life-saving antibiotics.” Drugs for cancer and rare diseases, he says, can cost up to £70,000 per treatment, whereas a full course of antibiotics can cost as little as £10. “There’s a mismatch between value to society and value to capitalist economics.”
He says that governments and regulatory bodies need to ensure the economic and regulatory environment is such that antibiotic discovery can again reach its pre-70s heyday. “We’ve been talking about this issue [tackling drug resistance] for 20 years and we’re still not seeing the type of momentum we need. Let’s hope we come up with the answers soon because modern medicine, and all the benefits that come with it, is hanging in the balance.”
The Review on Antimicrobial Resistance (AMR) chaired by economist Jim O’Neill, appointed by David Cameron to find solutions to the antibiotic crisis, has published three papers since December 2014. Here are some key figures from their research:
10 million The number of people who will die every year due to AMR by 2050.
90% of these deaths will be in Asia and Africa.
$100 trillion, the estimated total GDP that will be lost globally by 2050 if AMR isn’t tackled.
$2bn, the size of the fund O’Neill says should be established to fund AMR research.
$2-3bn, the reward O’Neill suggests drug companies are paid for launching a new antibiotic on a not-for-profit basis.
Source: The Guardian