Why New Antibiotics Never Come to Market

In the murky depths of Lake Michigan, around 15 feet below the surface, Brian Murphy is examining the various thickets of seaweed and vibrantly coloured sponges clinging to the sides of an old wooden cargo ship.

Clad in scuba gear, with an air tank attached to his back, a casual observer might mistake Murphy for a particularly intrepid archaeologist. But rather than examining the artefacts hidden away among Michigan's estimated 1,500 shipwrecks, Murphy is searching for new antibiotics, an ongoing treasure hunt which has seen him dive to depths of up to 130 feet in some of the most extreme locations on the planet.

"It's a huge gamble," he said. "We look for unique environments, and we just have to hope that the evolutionary pressures driven by the challenges of trying to survive in these conditions will yield microorganisms which can produce new drug leads. But we have no idea what we'll find."

The costs of such ventures, which have taken him across the globe from Thailand to Iceland, can stretch to tens of thousands of dollars. And with this brings pressure. Any organization willing to stump up such money will demand returns on their investment, but nature doesn't always play ball.

New antibiotics are generated naturally over time by bacteria, as weapons in their ongoing chemical warfare against other microbes. Predicting where and when they can be found relies mostly on good fortune and following a hunch. Murphy's hunch is that the bacteria which live on freshwater sponges could be a hive of new chemicals. "We don't know a huge amount about these species," he said. "But the only way to find out if there's anything there is by actually diving down there and carving them off with a knife."

But even if these sponges yield the antibiotics of the future, there are seemingly endless roadblocks that prevent us from actually using them to cure disease.

Murphy, an energetic 34-year-old from the University of Illinois with a thirst for adventure, is part scientist, part explorer. He originally wanted to be a firefighter, before he discovered biology could be just as exciting.

Bioprospecting—the technical term for the quest to find the drugs of the future—can be frustrating, but it's never boring. Sometimes it's even dangerous.

"We try to do really safe dives but it can be tough," he said. "There's been times diving in Vietnam when it's been particularly hazardous. Out there people sometimes just throw stuff overboard without really thinking twice. You end up navigating these shallow waters, with fishing nets sticking out all over the place, and at the same time you're trying to avoid these fields of stinging jellyfish with ten feet long tentacles."

Compared to recent expeditions to the sub-zero waters of the Arctic, the Great Lakes are a considerably less exotic location for medicine hunting. But they may hold the solution to tackling an ancient killer, a disease that has been the scourge of mankind for most of recent human history.

In April, Murphy and his colleagues discovered two new chemicals, called diazaquinomycins H and J, from a bacterium living in the waters of Lake Michigan, just off the coast of Milwaukee. Although the research is still in the earliest stages, they work with surprising potency against even the most multi-drug resistant strains of tuberculosis.

Mycobacterium tuberculosis is a bacterial infection that attacks the lungs. It originated in cattle before crossing over into humans around seven thousand years ago due to the increased milk consumption in our diets.

The discovery of antibiotics has kept tuberculosis largely under control for the past century, but the tides are turning with ominous speed. The emergence of new drug-resistant strains killed more than 210,000 worldwide in 2013 alone.

Murphy is investigating whether his new anti-tuberculosis chemicals work in mice that have been infected with the disease. If they continue to be effective in treating tuberculosis, they may prove candidates for an early stage clinical trial.

But this is just the start of a long and drawn out process which may still see them fall by the wayside just like so many promising medical discoveries over the past two decades.

As Murphy was announcing his discovery, a group of scientists, policy makers, and industry representatives had gathered in the university town of Uppsala in Northern Sweden to discuss solutions to a growing global healthcare emergency.

The facts presented were stark and chilling. The antibiotics that have protected us from an array of lethal microbes for more than half a century are rapidly becoming ineffective. And the blame rests entirely at our own door. Rampant, irresponsible overuse of these miracle drugs, to the extent that more than 63,000 tons globally are pumped into livestock production every year, has driven the evolution of a new breed of superbugs. Before long the world may be faced with a situation last seen in the pre-penicillin era when even the most minor infections, such as those resulting from a child's grazed knee, could prove life-threatening, and every operation was fraught with danger.

The annual death toll from bacterial infections is 700,000, according to the O'Neill review on Antimicrobial Resistance, a project commissioned by the British government. But many believe this figure to be a gross underestimate.

"If you have a heart valve that needs to be replaced, but you get a bacterial infection and die of that, your doctors will write down natural causes," said Professor William Fenical at the Scripps Institute of Oceanography in San Diego. "So it slips under the radar."

It's estimated that more people will die from bacterial infections than cancer by 2050. The trend was obvious. The conclusion in Uppsala was simple: The world needs to start developing new antibiotics, and fast.

But where will the money come from?

Fenical, the professor at Scripps Institute of Oceanography in San Diego, is one of the original marine biomedicine pioneers. He began investigating the ocean's potential to provide cures for disease in the late 1960s, long before anyone considered it as a science at all. Having spent most of his life living by the Californian coast, he describes himself as a chemist with an inherent curiosity about the ocean.

"We have 36 phyla on planet Earth," he said. "The phyla is the fundamental unit of life. Seventeen of them exist on land, but 34 exist in water. So it makes more sense to look for antibiotics in the oceans, rivers and lakes, as your chances of finding new chemicals are double."

In 2013, Fenical made one of the most interesting antibiotic discoveries in recent years off the coast of San Diego. A bacteria living in the sediment on the Pacific Ocean floor was producing a compound called anthracimycin. Fenical soon found it was capable of attacking the bacteria MRSA, a hospital superbug which is notoriously difficult to treat.

But in many ways, discovering antibiotics is the easy bit. Finding someone interested in investing in developing them is a far greater challenge. Two years have gone by since Fenical identified anthracimycin and no one has shown any interest in taking it from the research lab to the clinic.

"We've discovered six antibiotics in the recent past," Fenical said. "Of those, three to four have serious potential as far as we know, including anthracimycin. But we have no way to develop them. There are no companies in the United States that care. They're happy to sell existing antibiotics, but they're not interested in researching and developing new ones."

Deterred by the spiralling costs of drug development, most large pharmaceutical companies abandoned their antibiotic programs by 1995. And little funding is available from the public sector.

Twenty-five years ago, the urgent need to find treatments for HIV became a politically charged battleground. Faced with intense pressure to deliver results, the US National Institute of Infectious Diseases became a center entirely dedicated to virology. This remains the case today, but there are now no national programs aimed at tackling drug-resistant bacteria.

"It's a serious medical emergency in the US and Europe but the behaviour of the politicians doesn't reflect this," Fenical said. "President Obama laid out a program to try and deliver new medicines, but Congress hasn't allocated any money to it."

Fenical's frustrations stem from the fact that developing new antibiotics is in some ways far easier than developing treatments for other diseases such as cancer. In the mid 1990s, he discovered a small jellylike animal, no more than six inches long, attached to the side of an underwater cliff just off the coast of the Philippines. Named Diazona angulata, the sheer fragility of its appearance made scientists wonder how it could possibly survive in the open ocean, but Fenical knew from experience that such soft-bodied creatures have typically evolved hidden chemical weapons for self-defence.

He found that it contained a chemical known as diazonamide A, which could kill colon cancer cells, typically one of the most difficult cancers to treat, even in miniscule amounts. And most promisingly, it used a mechanism of action never seen before. "We had the pharma industry literally standing by," Fenical remembers. "We all thought we were on the verge of developing a whole new set of anti-cancer drugs."

Divers soon returned to Philippine waters, but it would take three years before they found the creature again. Despite their best attempts, they were unable to collect enough species to obtain sufficient amounts of the precious chemical.

It was the second disappointment of the decade for Fenical, who had discovered another potential cancer drug called elutherobin, found in a particular type of soft coral, which appeared to be highly effective against breast cancer. But this time, attempts to convert the finding into a medicine were blocked by conservation laws.

"We would have needed many kilograms of these substances in order to produce a drug," he said. "But once again we simply couldn't get enough of the material. No one's going to let you tear up a beautiful coral reef in order to do that."

Producing antibiotics, on the other hand, is far less environmentally invasive. All scientists need is to collect a few cells of the antibiotic-producing bacterium, which can then be cultivated en masse, enabling the production of the chemical on an industrial scale.

Having made a potentially enormous breakthrough in tuberculosis research within just a few months of investigating Lake Michigan, Murphy is keen to sample the rest of the Great Lakes. But with a lack of funding, he's turning to the general public to help him out.

"Before we dive anywhere, we always talk to the local divers to find out about what's out there," he said. "Some of these guys spend more time underwater than on land. So we had the idea, why don't we get them to collect the sponges and specimens growing in these lakes and send them back to us?"

Within just a couple of months, his team has already received around 40 samples ranging from the Hudson River in New York to Lake Huron. Categorizing them all, identifying the bacterial species which lie within, and most importantly the chemical they produce, will take weeks and months. Murphy is indebted to a small army of undergraduates and volunteers which help with this lengthy process. But as tedious as it is, they know the solutions to some of the world's deadliest bacterial infections may lie within.

The problem is that the money to do anything about them simply isn't there.

For any discoveries that Murphy makes, the road ahead is paved with obstacles. Safety testing, animal testing, and then finally, the hope that a drug company and its investors can be persuaded to gamble hundreds of millions on the chemical passing the multiple stages of human clinical trials, before it can be turned into an over-the-counter product.

The odds seem slim, but with the annual global mortality rate from antibiotic resistance predicted to hit 10 million in the next 35 years, scientists remain hopeful that the politicians will come to better agreements on how to finance antibiotic development. The question is, will they get around to doing so before it's too late?