As Big Pharma Abandons Antibiotic Research, Scientists Turn To Lizards, Graves, and Fungus For NewCures

As Big Pharma Abandons Antibiotic Research, Scientists Turn to Graves, Lizards, and Fungus for New Cures

Inside the Global Scavenger Hunt to Beat the ‘Antibiotic Apocalypse’

Go to the profile of Chris Baraniuk

Chris Baraniuk May 1

It’s said that for nearly 200 years, residents of a small rural area in Northern Ireland called Boho (pronounced “bo”), have practiced a strange and solemn pilgrimage to a local chapel. But they don’t come to pray within the chapel walls. Instead, they’re here for the dirt outside.

The Sacred Heart Chapel’s churchyard contains the centuries-old grave of Father James McGirr, a former priest. The soil above his body, it’s believed, has healing properties. The sick and ailing take a pinch of the stuff, pray with it for four days, then bring it back.

The “Boho cure,” as it’s known, is still popular today, and those who practice it hope it will heal anything from brain hemorrhages to cancer. John Corrigan, an elderly local man known as “the merchant” for his business acumen, says that over the years, he has fetched spoonfuls of the soil for various people in need.

Though the cure may be nothing more than a manifestation of the placebo effect, Corrigan says he’s convinced “that there is definitely power in it.” Thanks to the Boho cure, he says, a friend of his regained consciousness after a brain hemorrhage.

And it’s not just locals who are interested in the Boho cure. In an October 2018 study, researchers claimed that a potentially new antibiotic-producing strain of bacteria had been found in the same churchyard soil. Corrigan, for one, is unimpressed with the analysis. “The blessed clay has nothing to do with science. It has to do with faith,” he says.

Today, humanity faces an invisible crisis: Antibiotics, which we use to fight infections ranging from pneumonia to chlamydia, are losing their efficacy. Prophylactic use of these drugs prevents infection from taking hold in the first place, making surgery and cancer therapies safe. It’s no exaggeration to say that antibiotics underpin huge swathes of modern medicine, says Richard Ebright of the Waksman Institute of Microbiology in New Jersey.

“[Without antibiotics] you can’t do surgery of any kind, you can’t do chemotherapy, you can’t do immunotherapy, you can’t do transplantation… All of the branches of medicine that exist and all of the drugs that are sold into those branches are absolutely dependent on the existence of antibiotics.”

Doctors worldwide are increasingly finding that the antibiotic treatments they prescribe no longer work. Infections worsen, perhaps causing sepsis, and can turn fatal.

Resistance is popping up everywhere. Hospitals in New York are currently battling an outbreak of Candida auris, a tenacious fungal infection that can be impervious to multiple antibiotics. In the U.K., among other places, urinary tract infections that stubbornly resist treatment have become increasingly common. And there is significant concern in Kenya, India, and across the developing world, where infectious diseases like gonorrhea and malaria are common. According to the World Health Organization (WHO), many drugs used to treat these illnesses are now “useless.”

“This is a crisis that has similarities to climate change. The major difference from climate change is there’s less recognition, and addressing it would be much easier.”

Antimicrobial resistance (AMR) is estimated to be responsible for the deaths of hundreds of thousands of people every year, and the problem is only getting worse. One much-cited estimate suggests the annual death toll from AMR could reach 10 million by 2050. AMR has a financial impact too — it already costs the European Union 1.5 billion euros ($1.7 billion) every year in healthcare costs and productivity losses. Sally Davies, the U.K.’s chief medical officer, has warned that we could be facing an “antibiotic apocalypse.”

The rise of AMR is attributed to a number of causes. Over time, bacteria naturally evolve resistance to pharmaceutical antibiotics, but we have exacerbated the problem by overprescribing those antibiotics, both in human medicine and by giving the same drugs to animals. And poor hygiene on a global scale continues to be an issue: Avoidable infections lead to the use of even more antibiotics.

Almost all of the antibiotics being prescribed today were developed decades ago. The last time researchers discovered a completely new class of medically tested antibiotics — a group of compounds that work in the same way — was the mid 1980s. We are sorely in need of a fresh class.

And yet the largest pharmaceutical companies have dropped or largely scaled back efforts to find and develop antibiotics. Their reasoning is as pragmatic as the effects are devastating: Developing new antibiotics is not a profitable business, not even in a global pharmaceutical industry worth close to onetrillion dollars. Any new antibiotic introduced to the market today would only be used as a last resort to avoid the development of resistance. As such, society faces a paradox: Those best positioned to develop new antibiotics have little incentive to spend the hundreds of millions of dollars required to do so.

“This is a crisis that has many similarities to climate change in that it’s a slow-moving crisis with potentially catastrophic consequences,” says Ebright. “The major difference from climate change is there’s less recognition of this issue, and addressing it would be so much easier.”

Cures — both spiritual and medicinal — have the power to attract great interest. The number of people coming to gather Boho soil has risen dramatically in recent months, according to residents. Some have clearly taken the recent study to mean the ritual is now backed up by data. But for researchers, it is the hope of a new drug, a new class of antibiotics, that has them excited.

These researchers are called “bioprospectors,” scientists who scour the world from mountaintops to seabeds, sifting through nature to discover potential new antibiotics. They are also reexamining huge libraries of existing data, hoping to uncover the vital chemistry we need to support modern medicine. For these scientists, nature and evolution remain our best hope. The key to combating AMR, they believe, is hidden in new, exotic sources of antibiotics. We just need to find them.

During the 1950s and ’60s, the “golden era” of antibiotics, large pharmaceutical firms like Abbott and Merck encouraged their staff to compete in a global scavenger hunt for the next class of drugs. Employees would bring back soil samples from places they visited on business or scoop up little piles of dirt from wherever they happened to be vacationing. Thanks to these bioprospectors, the companies’ libraries of new chemicals grew vast: hundreds of thousands of different bacterial strains and associated compounds.

Antibacterial compounds attack and kill pathogenic bacteria in a variety of ways. They might destroy bacterial cell walls or debilitate internal components. The different mechanisms of attack separate antibiotics into distinct “classes.” There are about seven or eight main antibiotic classes, broken down further into specific compounds. It took huge amounts of time and money for companies to develop the antibiotic drugs used today — and build a market currently worth about $45 billion.

But over time, the discovery of new strains and compounds slowed dramatically and the field of antibiotics turned unexpectedly bleak. The “rediscovery problem” — finding the same compounds over and over — has now plagued the field for decades. In the 1990s, pharmaceutical companies tried another approach: genomics. This involved analyzing the DNA of pathogens to find novel ways of attacking them chemically. Researchers then searched their libraries for compounds that could carry out these attacks. But this method has yielded far less success than hoped.

As a result, some of the world’s largest pharmaceutical companies are disinvesting from efforts to discover and market new antibiotics, even as the threat of resistance grows. In 1990, there were about 20 major companieswith antibiotic discovery programs. Today, there are fewer than five. Between 2017 and 2019 alone, four major firms shut down their work in this area. Allergan was one of them, as was Novartis.

“We decided to prioritize our resources in areas where we believe we are better positioned to develop innovative medicines for patients,” a Novartis spokesperson said in a statement.

A few big pharmaceutical companies are hanging on, including GSK and Merck. “We do invest even in early stage approaches,” says Merck’s executive director of infectious diseases Todd Black. “But we haven’t seen anything that’s had a breakthrough yet.”

Even pharma companies appear to be acknowledging that the market alone won’t solve the resistance problem.

Jim O’Neill, a British economist and head of a commission that recently investigated the threat of AMR, published a review of the problem in 2016. He and his colleagues found that between 2014 and 2016, the number of antibiotic compounds in development pipelines had fallen from nearly 800 to just 50. Fewer compounds in the pipeline means fewer chances of developing a drug that could beat resistant bacteria. The situation has become so desperate that in March this year, O’Neill advocated nationalizing part of the pharmaceutical industry to effectively force it back into the business of developing antibiotics.

The U.K. government is already experimenting with the market. In January, the country announced a new plan for tackling AMR, including a scheme in which the National Health Service will attempt to calculate the value of antibiotics both for individual patients, as well as their larger impact on AMR.

Other radical ideas are also being floated in the U.S. and Europe, including tax incentives and financial rewards for whoever comes up with the next penicillin or streptomycin. Even pharma companies appear to be acknowledging that the market alone won’t solve the resistance problem. Drug industry representative Thomas Cueni recently argued that governments and private industry would have to work together to make the drugs we need. In February, a number of pharmaceutical companies and public health experts wrote a letter to U.S. senators urging them to create a package of financial incentives specifically designed to boost antibiotic development.

At this point, though, all these efforts remain largely unproven.

But many scientists refuse to give up. And instead, they’re turning to old-fashioned bioprospecting to find a cure.

Inthe summer of 2015, microbiology researcher Gerry Quinn of Ulster University came to the churchyard of the Sacred Heart Chapel looking to put faith to the test. Having grown up in the area, Quinn was familiar with stories about Irish folk cures. And as an academic, he knew that antibacterial properties can occasionally be found in unlikely soil and clay deposits associated with local lore. Kisameet clay, used for centuries by First Nations people in British Columbia as a remedy for ailments including stomach disease, was recently found to contain compounds that can fight pathogenic microorganisms.

During his visit, Quinn inspected tiny cloth bags of soil that had been left on the grounds, perhaps by locals for cure-seekers to take. He probed inside the bags with a sterile spatula, lifted a couple tablespoons’ of soil into a sterile tube, and then brought the sample to his lab at Swansea University in Wales, where he was working at the time. There, a single gram of the sample was diluted and shaken to separate out any potential bacteria. (Quinn later returned the soil, conforming both with tradition and scientific ethics.)

Quinn took some circular petri dishes and filled them with a layer of nutritious orange agar to feed a hungry bacterial colony. The processed sample from the Boho soil was then deposited on top. Before long, bacterial colonies bloomed.

There are more than 500 known species of Streptomyces and a handful of them are the source of between 70 and 80% of all antibiotics ever developed.

After about three days of isolation, the colony had formed a white-ish mass across the bottom of the plate. Quinn knew there was something potentially promising here: a strain of the bacteria Streptomyces. On a recent visit to the lab, I examined — and sniffed — the substance. It smelled like an old damp mop, though there was something herby and savory there as well.

Though Streptomyces strains are incredibly common, they have also proven very useful. There are more than 500 known species of Streptomyces and a handful of them are the source of between 70 and 80% of all antibiotics ever developed. Millions of lives have been saved due to this group of bacteria alone. Streptomycin, one of the first antibiotics, has been used to treat tuberculosis, rabbit fever (tularemia) and Yersinia pestis — commonly known as “plague.”

Quinn thinks his strain is a new species and, in homage to its odor, he has named it Streptomyces sp. myrophorea — “myro” is the Greek word for “fragrance.” More detailed genetic analysis will be needed in order to confirm whether Quinn’s strain is truly distinct, but what ultimately matters is the antibiotic it produces.

It’s thought that Streptomyces and other bacteria produce antibiotics as part of a defense mechanism against competing microbes. By adding a pathogen to Streptomyces petri dish colonies, scientists can sometimes provoke the strain into spewing out precious antibiotics as it fights off invaders.

When this happens, the result is immediately visible, even without a microscope. “You start to see a zone of organisms not growing around them,” explains Quinn. The inhibition zone around antibiotic-producing bacteria is often called a “halo.”

With the help of his colleague Luciana Terra at Swansea University, Quinn found that the Boho Streptomyces inhibited the growth of three important pathogens, one of which, Acinetobacter baumannii, has been known to cause serious infections in hospitals and is on WHO’s priority list of antibiotic-resistant bacteria.

Now, Quinn has to identify the compound his strain is pumping out, and determine its exact chemical makeup. The compound could be something completely new, with a never-before-seen way of attacking pathogenic bacteria. If that were the case, it would represent a new class of antibiotics.

“That,” says Quinn, “would be awesome.”

To enter the market, Quinn’s process would have to be scaled up drastically. Scientists would have to find the most effective way of encouraging the Streptomyces strain to produce the new compound in large quantities. Then, they’d have to test that compound in human cell cultures and animals to ensure, among other things, that it isn’t highly toxic. And the drug would have to perform as intended during a series of clinical trials in humans before finally coming to market. The whole process would take many years — and millions of dollars. In total, Quinn is examining eight different strains that all seem to have antibacterial or antifungal effects. If on the off chance he has discovered a new, safe, and marketable antibiotic at Boho, it will be the first such discovery in nearly four decades.

Quinn is one of thousands of researchers bioprospecting around the world. His colleague Terra has personally taken samples from the Gobi desert and Tibetan plateau. Others have examined antibiotics produced by insects, including spined soldier bugs. Scientists have even extracted antibiotic compounds from the blood of Komodo dragons.

Bioprospecting can be controversial. Critics have labelled it “biopiracy,” noting cases where researchers have identified indigenous resources and repurposed them for a broader public while failing to compensate the communities from whence they came. One good example is the neem treeAzadirachta indica, known for centuries as a healing tree in indigenous Indian cultures. A European patent for a fungicide developed from the tree was deemed to have appropriated the knowledge of the ancestral people and was overturned after a decade-long legal battle. Increasingly, many scientists argue that compensation is both morally and legally justified.

Today, many bioprospectors are conscious of these issues and follow ethics codes designed to protect indigenous knowledge and culture. Furthermore, the 2010 Nagoya Protocol, part of the international Convention on Biological Diversity, aims to ensure the “fair and equitable” sharing of discoveries made from biological genetic resources. More than 100 countries have signed up for it.

Linamaría Pintor-Escobar, a microbiologist from Edge Hill University in England, is part of a small team examining Streptomyces in a Colombian mountain park. She has identified two strains with extremely similar genomes, but which are effective against different pathogens, and have distinct bacterial colonies. Identifying subtle genetic differences between the strains could help scientists discover previously unknown mechanisms of antibiotic production.

Meanwhile, Rebecca Devine from the University of East Anglia in England has isolated Streptomyces bacteria from an unlikely source: African ants that live inside the large, swollen thorns of a leafy plant. The ants cultivate a fungus that feeds them, but they need bacteria to help protect the fungus. Among the bacteria found in the cultivated fungus are novel strains, which Devine and her colleagues have shown produce unique antibiotics called formicamycins. Some of these compounds have been found to be effective against a different fungus known to infect humans.

“Nature is a far better chemist than we can ever be.”

“It’s quite a rare fungus infection at the moment; it really affects immune-compromised patients,” says Devine. “But it’s drug resistant and if you do get an infection there’s no treatment.”

Katherine Duncan of the University of Strathclyde in Scotland has been researching bacteria hidden in sediment found at the bottom of remote oceans. Duncan, like many of her colleagues, believes that the next antibiotic breakthrough will be found out in the world rather than in a lab. As she puts it, “Nature is a far better chemist than we can ever be. These tiny microscopic organisms are actually manufacturing something that a team of chemists can struggle to do — and I can say that because I’ve got a chemistry background.”

But even if these bioprospectors find what they’re looking for, the path to market remains challenging. Only about 1% of bacteria found in the wild will grow in the unfamiliar environment of a laboratory. To try and tease out more bacteria from the soil, researchers have come up with devices called “ichips”that allow the microbes to flourish in little chambers housing more familiar, natural materials. It’s like bringing the outdoors into the lab. One project has already found a promising new antibiotic called teixobactin through this technique.

Researchers are also turning to metagenomics, a method of sampling DNA from an assortment of microbes found in an environmental sample, like rainwater or dirt. In 2018, this technique was applied to 2,000 soil samples, revealing a previously untapped groups of related genes. This DNA, which came from a desert soil sample, was cloned in a Streptomyces strain that can be grown in the lab. The antibiotic it produced was effective against the resistant pathogen MRSA, and appears to be a member of a completely new class called malacidins.

Another approach is to undertake a more systematic examination of existing libraries of compounds that have never been properly explored for antibiotic potential. Laura Piddock, director of scientific affairs at the Global Antibiotic Research and Development Partnership (GARDP) is leading a new effort to do just that. The search will seek out viable results from large libraries containing thousands upon thousands of compounds, some of which have never before been screened.

Ebright lauds the efforts of researchers who have continued bioprospecting. But science can only do so much. If pharmaceutical companies continue to turn their backs on the field, researchers’ discoveries and hard work may be nothing more than a “a moot point,” as Ebright puts it. Without the necessary investment to develop, test, and market these new antibiotics, potential breakthroughs will never leave the lab.

All the while, the resistance crisis only worsens.

When I visited Boho in the early spring of 2019, I stopped by the Linnet Inn, the nearest pub to the Sacred Heart Chapel. Owner Dessie McKenzie has watched the number of visitors grow since the publication of Quinn’s Streptomyces study in 2018. McKenzie’s pub, with its thatched roof, happens to be roughly 200 years old — the same vintage, supposedly, as the Boho cure.

It was a Thursday afternoon and McKenzie had just opened the place up for the night’s business. Perched on a bar stool, I asked him if he believed in the fabled remedy. “You have to be open-minded,” he said. He’s heard of numerous people cured of their illness thanks to the soil.

Whatever is happening in the soil in Boho, McKenzie said that one thing has struck him lately: the lengths people will go to find a cure for their illnesses. “Just looking for one, any little shred of light or scrap of hope that they could sustain their life,” he said.

With the rise of AMR, it is a plight that will only become more common.

There’s no evidence that taking the Boho soil home and praying with it can heal our ills. But the bacteria in that soil — or from some other unlikely source around the world — may yet provide us with the new antibiotics we desperately need. It would be a miracle of sorts.