ANTIBIOTICS have changed what it means to be human. Few of us remember when bacterial infections from a wound, a bout of flu, sex or childbirth could kill anyone, at any time. This constant risk of death was just something we lived with. When antibiotics became common in the 1950s, that ended – and the drugs also opened a new frontier of surgery and therapy for other diseases.
But the bad old days are returning as bacteria evolve to resist antibiotics. Just last week, of two women in the UK infected with resistant, or “super”, gonorrhoea. Thankfully they were cured, but others may not be so lucky.
You have probably heard about this problem – . After urgent alarms were sounded in 2015, governments and charities finally ploughed more money into drug discovery. These efforts are starting to bear fruit, but there is a larger problem – one of economics, not science.
Advertisement
The issue is that pharma firms must recoup their investment in developing drugs, but antibiotics are the antithesis of a bestseller. They are taken for days or a few weeks, whereas diabetes or heart drugs are highly profitable because patients can use them for life. Plus, new antibiotics can’t compete with older, cheaper drugs that still work and are no longer patented.
“Only 56 experimental antibiotics world wide have progressed as far as tests in people”
By the time resistance to the old antibiotics builds up and doctors must prescribe new, expensive ones, their patented life may be almost over, leaving little time for their owner to turn a profit. Novel drugs must also be kept in reserve or used sparingly, to stop bacteria building a resistance to them, too.
As a result, says Kevin Outterson of Boston University, US sales of all antibiotics still under patent totalled just $700 million in 2017 – less than what a single new cancer drug makes in a year. This is having a dire effect on the field. Outterson, who runs CARB-X, a global consortium that encourages the development of antibiotics, says microbiologists aren’t interested in tackling bacteria. “The careers and money are in things like Ebola.”
Firms have been abandoning work on the drugs for years. In 2018, two more, Sanofi and Novartis, dismissed their antibiotic research teams, leaving only GlaxoSmithKline, Pfizer and Merck, and they have reduced their programmes and aren’t launching new studies. Now, most drug discovery is done by small, struggling biotech firms. Bad profit prospects meant those working on antibiotics lost some 50 to 75 per cent of their stock value in 2018, even as investment in other firms grew.
Push and pull
This market failure is creating a further crisis. The closures of antibiotics R&D departments had, by the start of 2018, left just some 800 experienced researchers working on antibiotics. “In 2018 alone, we lost 200 of those. It’s like losing a language,” says Outterson. In five or 10 years, he fears, the last big firm may abandon antibiotics, and these vital researchers will be extinct.
Indeed, the pipeline for new drugs has been drying up. Last month, found that only 56 experimental antibiotics worldwide have passed animal tests and are now undergoing trials in people – which, . Of those 56, only 30 per cent work in novel ways. That is a concern, because drugs that operate in the same way as existing ones may not be able to defeat resistance (see “New ways to kill infections”).
In 2015, a commission set up by the UK government and headed by Jim O’Neill, a former banker, estimated that losing antibiotics would cost society trillions of dollars. It called on governments to instead invest billions in two kinds of incentives for new antibiotic development: “push” incentives funding research to discover new kinds of drugs and “pull” incentives to make it profitable to develop them.
The push part is finally happening. Last year, O’Neill calculated that, if it continues, new funding should add up to the $2 billion over 5 years his commission called for – and this money is funding new drug discoveries.
In contrast to the 56 older drugs in human trials, there are 98 starting to be tested in animals, and nearly two-thirds attack bacteria differently from older drugs, increasing their chance of success. But “without the pull incentives, this research will just accelerate into a wall”, says Outterson.
O’Neill estimated that government funding of between $1.6 and $3.7 billion per year could pay a firm to do the expensive tests of novel antibiotics in people. The government could then own the patent or some rights to market the new drug. The firm recoups its investment; the drug is used only as needed.
In May this year, the UK government will launch the first-ever such “pull” project, paying two companies to bring new anti-microbial drugs to market. The price of the drug will be “delinked” from what the company needs to recoup its investment, so there is no pressure to market the new drugs aggressively, and they can be saved for the cases that resist all other treatments.
The newly elected US Congress also plans to discuss such “market entry reward” schemes for new antibiotics, including an idea called “play or pay”, in which drug firms that aren’t working on antibiotics have to pay into a fund to reward companies that do. Existing legislation allowing government agencies to reward firms that develop biodefence drugs for which there is no market, such as anthrax vaccines, may also be pressed into service.
If that sounds like it will cost taxpayers a pretty penny, compare it with  – $2.2 billion a year in the US, according to a study last March. In a patented antibiotics market worth $700 million in the US, another $700 million might get things started, says Outterson.
“There are 98 drugs starting testing in animals, most of which attack bacteria in new ways”
We might not even need to pay directly. In November, a drug called zoliflodacin passed tests showing it was safe and effective in humans against gonorrhoea, which has become so antibiotic-resistant that some infections are now almost incurable.
Many promising new drugs get this far and no further, but this one is already set to enter the big, expensive tests needed before it can be licensed. The trials will be financed by Entasis, the US company developing the drug, and also by governments and other donors organised by GARDP, a global organisation promoting antibiotic development.
If it passes, Entasis will market the drug in 34 rich countries, while GARDP gets marketing rights in 166 poor ones. Entasis makes the profit it needs, while the gonorrhoea epidemic in poor countries gets an effective drug – under tight control.
Ultimately, says Outterson, if these schemes don’t work fast enough, governments will have to take over the business of providing antibiotics. It wouldn’t be the first time they have done this kind of thing. Until the 1980s, government agencies produced the public-health vaccines that defeated diseases such as polio, measles and smallpox, as a public good, like roads and schools.
Ideology has frowned on governments messing with markets. But it may take only a few more untreatable cases of gonorrhoea or urinary tract infection to make ideologues sing a new song.
New ways to kill infections
Fighting antibiotic resistance requires a new arsenal. Here are some possible ways to shore up our defences.
Sequences in the soil
Antibiotics were originally evolved by microbes trying to ward off bacteria, and we have discovered only a few of the ones that exist in nature.
In June, a team in California , 360 of which were new to science, and found genetic code for several substances that look like antibiotics.
Better together
Taking two drugs together should, in theory, make it harder for bacteria to resist both. In July, a group in Germany .
They found that, in most cases, the drugs impeded each other. But some worked better together, including one antibiotic and vanilla.
Set a bug to catch a bug
Several companies are investigating how competing bacteria and other microbes might dislodge infections.
SciBac in Burlingame, California, is developing microbes that stop Clostridium difficile, which causes diarrhoea, from colonising the gut.
And Vedanta Biosciences in Cambridge, Massachusetts, is searching for “good” gut bacteria that stop °ä.Ěý»ĺľ±´Ú´Úľ±ł¦ľ±±ô±đ by outcompeting it after they are swallowed.
Borrow your immunity
It takes weeks for us to make antibodies to stop infections. Firms are working on synthetic antibodies, including a type made by llamas and similar animals. These antibodies are on bacteria.
Bacterial Achilles’ heels
Existing antibiotics attack bacteria at a small number of vulnerable sites on their surface, but once bacteria acquire a gene to protect that site – by destroying the antibiotic, or stopping it binding – the drugs stop working.
A number of firms are looking for drugs that attack new targets, such as the parts of bacteria that synthesise ribosomes and .
