Such a case is a nightmare for doctors and health officials. In August 2016, doctors isolated the bacterium Klebsiella pneumoniae from a wound in a woman in the US state of Nevada. This hospital germ was resistant to 26 antibiotics, and even treatment with the reserve antibiotic colistin did not work. The woman died shortly afterwards of blood poisoning.
In Germany, too, people are dying from pathogens that conventional antibiotics can no longer harm, as Andreas Peschel from the German Center for Infection Research (DZIF) emphasizes. “Such cases will increase,” says the Tübingen microbiologist.
A study published in the journal “The Lancet” at the beginning of 2022 shows the extent of the problem: According to this, more than 1.2 million people worldwide died directly from an infection with an antibiotic-resistant pathogen in 2019. With almost five million deaths, such an infection was at least partly responsible for the death, writes the team led by Christopher Murray from the University of Washington. This makes antibiotic resistance one of the most common causes of death worldwide.
The authors demand that new antibiotics urgently need to be developed and brought to market. But that’s exactly what’s lacking, and has been for decades. International organizations such as the World Health Organization (WHO), the EU and the G7 – most recently at their summit in June at Schloss Elmau – also recognize the problem. But hardly anything happens. If that doesn’t change, a report commissioned by the British government warns, the number of people dying from such infections could rise to ten million a year by 2050.
Why is? Bacteria in particular have evolved substances to keep competing bacteria in check. So far, only a tiny fraction of these antibacterial substances is known. At the same time, the microorganisms are constantly developing ways to protect themselves and become resistant.
The British physician Alexander Fleming came across the first antibiotic, penicillin, which originated from a fungus, by chance in the late 1920s. In the decades that followed, researchers discovered such substances by cultivating bacteria – mostly from soil samples – in the laboratory and then testing whether the substances they produced were effective against pathogens. Especially from the 1940s to the 1960s, pharmaceutical companies brought many antibiotics onto the market.
“In the pre-antibiotic era, more than half of deaths were due to infections,” Cook and Wright write. The new drugs would have drastically reduced mortality from infection and thus increased human life expectancy. Controlling infection is still critical for many basic medical applications today, from surgery to chemotherapy to organ transplants.
But the golden era of antibiotic research is over. The rate at which new drugs are coming to market has fallen to its lowest level in 80 years, Cook and Wright write. The last active ingredient with a new active principle to be approved as an antibiotic was discovered in the 1980s, as a team led by Rolf Müller from the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) wrote in the journal “Nature” last year.
According to a database, 73 substances are currently being tested on humans in clinical trials; 54 of them in early phases where safety is checked. With about five exceptions, all of these substances are further developments of older antibiotics, says Müller. “That doesn’t really help. We have to find new basic chemical structures.”
It is by no means certain that one of the drugs currently being tested will also be approved. “If things go badly, none of them make it,” says Yvonne Mast from the Leibniz Institute DSMZ – German Collection of Microorganisms and Cell Cultures in Braunschweig. Because the substances not only have to be effective, they also have to be well tolerated. “Most substances usually don’t make it to approval,” says Müller.
There is a reason for the lack of supplies for years: “Big industry has withdrawn for economic reasons,” says Müller. Antibiotics are too cheap and those treated usually recover quickly. In addition, if a new type of effective antibiotic were to come onto the market, it would probably only be used in emergencies to make it more difficult for resistance to develop. This also affects the profits of the manufacturers.
According to Müller, drugs for diseases such as high blood pressure, which are usually taken for life, or medicines that can be sold at high prices, such as cancer therapies, are much more worthwhile for pharmaceutical companies. The number of cancer drugs in the pharmaceutical companies’ pipeline is currently estimated at more than 1,300.
New strategies against resistant pathogens are required. There are definitely ideas and initiatives for finding new antibiotics at universities and other research institutes: A team led by Sean Brady from Rockefeller University in New York came across two novel substances using a specially developed method, which will be published in the renowned specialist journals “Nature ‘ and ‘Science’. The approach uses the fact that more and more genes for antibacterial agents have been decoded.
Brady proceeded as follows for the substance presented in “Science”: First, the team analyzed around 10,000 known bacterial genomes for hereditary factors that contain the blueprint for so-called lipopeptides. This group of substances can affect bacteria via various mechanisms. Almost 3500 groups of genes appeared promising because of their size and structure.
A team led by Martin Grininger from the University of Frankfurt presented a method in the journal “Nature Chemistry” for equipping antibiotics and other active substances with fluorine atoms and thus specifically changing their pharmacological properties: such as binding to target molecules, stability and availability in the body and the effectiveness. The feasibility of the approach has been demonstrated with the antibiotic erythromycin, but pharmaceutical tests are still pending.
In the fight against bacterial pathogens, there are alternatives to antibiotics. New vaccinations, such as an mRNA vaccine against tuberculosis, should help. Hopes also rest on synthesized antibodies that neutralize certain bacteria. And bacteriophages have been rediscovered. These are viruses that multiply in bacteria until they cause the bacteria to burst.
There are new ideas and approaches on how to come up with new active ingredients. But who is going to bring them through clinical studies to market maturity? Universities have neither the money nor the expertise for this. Müller estimates that such developments will take ten to twelve years, and the costs at one to two billion euros per drug.
As big pharma pulled out, small companies would have to fill the gap, Cook and Wright write. In view of the major risks, such as failed approval, financial incentives must be created for them. Great Britain, for example, wants to support companies that produce the antibiotics they need with a premium, regardless of sales figures. According to Müller, there are comparable projects in Sweden and a similar approach is being prepared in the USA.
In Germany, too, public funding is needed to boost antibiotics research, says Peschel. “There must be government incentives. That’s far away in Germany.” In order to tackle the problem strategically, Müller suggests bringing everyone involved together so that resources can be used more efficiently: drug researchers, physicians and representatives of the pharmaceutical industry.
Even if there were funding and the cooperation came about: Peschel does not expect immediate success: “Research on active ingredients takes many years.” What is discovered now would not be on the market for at least ten years.
