Why new antibiotics do not enter the market

In the dark depths of Lake Michigan, at a depth of 5 meters, Brian Murphy [Brian Murphy] examines thickets of algae and brightly colored sponges holding the sides of an old wooden cargo ship.

Equipped with equipment for divers, with an oxygen tank on the back, Murphy can be confused with a fearless archaeologist. But instead of exploring the artifacts hidden among the nearly 1,500 sunken ships, Murphy is looking for new antibiotics. This treasure hunt makes him dive to a depth of 40 meters in the most extreme places on the planet.
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“This is a big risk,” he says. - We are looking for unique natural conditions and we can only hope that the evolutionary impacts resulting from problems with survival in such conditions will lead to the emergence of microorganisms that can give us new ways to create drugs. But what we find, we do not know. "

The cost of such events, forcing him to travel across the globe from Thailand to Iceland, can reach tens of thousands of dollars. And they have a big responsibility. Any organization that can spend so much money will demand a return on investment, but nature is not always ready to play by the rules.

New antibiotics appear naturally due to bacteria that use them as weapons in chemical warfare with other microbes. Predicting where and how they can be found can only be achieved with great luck and foreboding. Murphy feels that bacteria living on sponges in fresh water can be a warehouse for new chemicals. “We don't know much about this species,” he says. “But the only way to find out if there is something is to dive in and cut them with a knife.”

But even if these sponges bring us antibiotics of the future, there are so many obstacles that will prevent us from using them to cure diseases.

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Murphy, an energetic 34-year-old man from the University of Illinois who loves adventure, combines the work of a scientist and a diver. At first he wanted to be a fireman, but then he discovered that biology could be just as interesting. Bioprospecting — the search for drugs of the future among biological sources — can be frustrating, but not boring. Sometimes they are even dangerous.

“We try very hard to dive safely, but sometimes it’s difficult,” he says. - In Vietnam, diving was especially dangerous. People there often throw garbage overboard without thinking. As a result, you are trying to swim through these shallow waters, where fishing nets stick up everywhere and at the same time avoid fields with jellyfish stinging with their three-meter tentacles. ”

Compared with recent expeditions to cold arctic waters, the Great Lakes are less exotic places to look for drugs. But they can find a tool to fight the ancient killer, a disease that served as the scourge of humanity for most of its recent history.

In April, Murphy and his colleagues discovered two new compounds, diazacquinomycins H and J [diazaquinomycins], thanks to bacteria that live in Lake Michigan, off the coast of Milwaukee. Although the study is still in its early stages, the compounds work surprisingly well even against drug-resistant tuberculosis bacteria.

Mycobacterium tuberculosis is a bacterium that attacks the lungs. It is believed that it originated in livestock, and then migrated to people about seven thousand years ago, due to the increase in milk consumption. [ According to other information , tuberculosis appeared much earlier, and got from a person to the cows - approx. trans. ]

The discovery of antibiotics in the 20th century made it possible to control tuberculosis, but the situation is changing very quickly. The emergence of new types of bacteria that are resistant to drugs, only in 2013 killed more than 210,000 people worldwide.

Murphy is investigating whether new compounds will work against tuberculosis in mice infected with the disease. If they continue to demonstrate effectiveness, they will be candidates for clinical trials.

But this is still the beginning of a long process with an unknown outcome, which could end in nothing, like many other promising medical discoveries made in the last twenty years.

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A group of scientists, regulators, and industry representatives gathered in the university town of Uppsala in northern Sweden to discuss the opening of the announcement to discuss possible solutions to an emergency that is brewing in medicine.

The facts were harsh and scary. Antibiotics, which have protected us from a large number of deadly germs for more than half a century, are rapidly losing their effectiveness. And you can only blame ourselves. The unrestrained and irresponsible use of these magical drugs, up to 63,000 tons of the annual use of antibiotics in animal husbandry, led to the evolution of a new type of bacteria. Soon the world may be in a situation that existed before the discovery of penicillin, when even the simplest infections, such as a ripped off knee, could be life threatening, and each operation carries a danger.

According to the report of the Antimicrobial Resistance project organized by the British government, 700,000 people die from bacterial infections every year. But many believe that this figure is greatly underestimated.

“If you need to replace a heart valve, but you die from a bacterial infection, doctors state death from natural causes,” says Professor William Fenikal from the Institute of Oceanography. Scripps in San Diego. “So these things go unnoticed.”

According to some estimates , by the year 2050 more people will die from bacterial infections than from cancer. The trend is obvious. The conclusion made in Uppsala was simple: the world needs to very quickly develop new antibiotics.

But where to get the money?

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William Fenikal, Professor of the Institute of Oceanography. Scripps in San Diego is one of the pioneers of marine biomedicine. He began to study the potential of the ocean to discover new drugs in the late 1960s, long before it was considered a science. After spending most of his life on the California coast, he describes himself as a chemist with an inherent interest in the ocean.

“There are several dozen biological types on planet Earth,” he says. - Type - the basic unit of life. Almost two thirds of them live in water, “Therefore, it is wiser to look for antibiotics in the oceans, rivers and lakes, since the chances of finding them there double.”

In 2003, off the coast of San Diego, Fenical made one of the most interesting discoveries in the field of antibiotics. The bacterium, which lives in bottom sediments at the bottom of the Pacific Ocean, produced the anthracemicin compound. Fenical soon discovered that it was capable of attacking the bacteria MRSA [methicillin-resistant Staphylococcus aureus; also this compound can kill anthrax - approx. perev.], resistant to antibiotics, living in hospitals, which is very difficult to treat.

But in a sense, it is easy to open an antibiotic. Finding someone interested in investing in their development is much more difficult. Two years have passed since the discovery of anthracysmicin, and no one became interested in transferring it from the research laboratory to the clinic.

“We have recently discovered six antibiotics,” says Fenical. - Of these, 3-4 have serious potential, including antrasymicin. But we are not able to develop them. None of the companies in the US are interested in them. They are happy to sell existing antibiotics, but are not interested in research and development of new ones. ”

Due to the rapidly increasing cost of drug development, most large pharmaceutical companies abandoned their antibiotic development programs by 1995. The private sector is not able to organize serious funding.

25 years ago, the urgent need to find a cure for HIV became a politicized battleground. The US State Institute of Infectious Diseases has become a virology center. Everything remains to this day, but today there are no government programs to combat antibiotic-resistant bacteria.

“This is an urgent medical need in the United States and Europe, but the behavior of politicians does not reflect this,” says Fenical. “Obama presented a new drug development program, but Congress did not allocate money for it.”

Phoenical's disappointment is growing from the fact that developing a new antibiotic is in some ways simpler than developing drugs for cancer-like diseases. In the mid-1990s, he discovered a small jellyfish, only about 15 cm long, attached to a submerged rock off the coast of the Philippines. The external fragility of a creature called Diazona angulata surprised scientists - it was not clear how it could survive in the open ocean. But Fenical knew from experience that such soft-bodied creatures often have chemical weapons for self-defense.

He found that the creature was armed with diazonamide A, even in minimal doses, to kill intestinal cancer cells, the most difficult type of cancer to treat. The fact that the creature uses a previously unknown mechanism was also promising. “Literally, the entire pharmaceutical industry was waiting for us,” Fenical recalls. We all thought that we were on the verge of developing a new type of cancer drugs. ”

The divers returned to the Philippines, but it took three full years until they found this creature again. And, despite all the attempts, they could not gather enough jellyfish to get the right amount of valuable substance.

This was the second disappointment in ten years for Phoenical, who discovered another potential cure for cancer, eluterobin [elutherobin], found in a type of soft coral, which showed high efficacy against breast cancer. But this time, the transformation of the find into medicine was prevented by environmental conservation laws.

“We needed kilograms of the substance to produce the medicine,” he says. - But we failed to collect it enough. No one will allow you to destroy beautiful coral reefs for this. ”

Antibiotic manufacturing, on the other hand, does not require an invasion of nature. All that is needed is to collect several antibiotic-producing bacteria, which can then be grown to organize the industrial production of a chemical compound.

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Having made a potential breakthrough in the study of tuberculosis in just a few months of research in Lake Michigan, Murphy enthusiastically seeks to explore the rest of the Great Lakes. But with no money, he decided to ask the public for help.

“Before diving, we always communicate with local divers to find out what they have already found,” he says. - Some of them spend more time under water than on land. And we decided, why do not we ask them to collect sponges and other species living in lakes, to send them to us then? ”

In just a couple of months, the team received 40 samples found in the area from the Hudson River in New York to Lake Huron. Breaking them down into categories, identifying the bacteria living in them and the chemical compounds they produce will take weeks and months. Murphy owes a small army of students and volunteers to help in this long process. But, despite the tediousness of the process, they know that the samples may contain drugs for the most deadly bacterial infections.

The problem is that there is simply no money to do something with them.

For any of the discoveries made by Murphy, the road to development is full of obstacles. Testing for safety, testing on animals, and the hope that pharmaceutical companies and their investors can be persuaded to put hundreds of millions of dollars on the fact that new compounds will go through all the stages of clinical trials before they can be turned into a retail product.

There is little chance, but since the number of people who die each year from drug-resistant bacteria in 35 years will reach 10 million , scientists hope that politicians will be able to agree on financing the development of antibiotics. The question is, can they do it before it is too late?