Experts have been discussing how infections with antibiotic-resistant bacteria could be treated in the future for years. There are a number of new approaches to this. However, there are no incentives to bring bactericidal active ingredients to market maturity.
Such a case is a nightmare for doctors and health authorities: In August 2016, doctors in the US state of Nevada isolated the bacterium Klebsiella pneumoniae from a wound in a woman. This notorious hospital germ, which the patient had probably contracted during a stay in India, was resistant to 26 antibiotics, even the reserve antibiotic colistin did not work. The elderly woman died shortly afterwards of blood poisoning.
The case shows where the world is heading right now. In the journal “Science Translational Medicine”, Michael Cook and Gerard Wright from Canada’s McMaster University warn of an imminent “post-antibiotic age”. Some infections that used to be routinely cured with medicines discovered in the 20th century could then no longer be treated. One is already confronted with it, writes the duo and refers to resistant variants of the hospital germ Acinetobacter baumannii or the tuberculosis pathogen Mycobacterium tuberculosis.
In Germany, too, many people die from pathogens that many antibiotics cannot harm, as Andreas Peschel from the German Center for Infection Research (DZIF) emphasizes. “Such cases will increase,” says the Tübingen microbiologist, “everything speaks for it.”
A study published in the journal “The Lancet” in early 2022 shows the extent of the problem: According to this, more than 1.2 million people worldwide died in 2019 directly from an infection with an antibiotic-resistant pathogen. 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 missing, 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 – recognize the problem. But hardly anything happens. If this doesn’t change, a report commissioned by the British government warns that 10 million people could die from such infections every year by 2050.
Bacteria, in particular, have evolved countless substances over billions of years in constant competition with each other to keep each other 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 – i.e. resistances.
The British physician Alexander Fleming came across the first antibiotic – penicillin, which originated from a fungus – by accident in the late 1920s. In the decades that followed, researchers discovered such substances by cultivating bacteria – usually from soil samples – in the laboratory and then testing whether the substances they produced combat pathogens. Especially from the 1940s to the 1960s, pharmaceutical companies brought many antibiotics onto the market – countless people benefited from them.
“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 infection-related mortality and thus significantly extended the lifespan. And for many basic medical applications – from surgery to chemotherapy to organ transplants – controlling infection is critical.
But the golden age of antibiotic research is long gone – the rate at which new drugs are coming to market has fallen to its lowest point 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 in human clinical trials – 54 of them in early phases testing safety. 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.”
And it is by no means certain whether one of the drugs currently being tested will actually pass the tests and be approved. “If things go badly, none of them make it,” says Yvonne Mast from the Leibniz Institute of the German Collection of Microorganisms and Cell Cultures, DSMZ for short, 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 they work well. The patients 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 is also reflected in manufacturers’ profits.
According to Müller, drugs for diseases such as high blood pressure, which are usually taken for life, are much more worthwhile for pharmaceutical companies. Or medicines that can be sold at high prices – such as cancer therapies that can cost more than 100,000 euros. This earnings potential is also reflected in the drugs that pharmaceutical companies have in the pipeline: The number of cancer drugs in clinical trials is currently estimated at more than 1,300.
In view of the worsening situation, new strategies are required. On the one hand, this involves discovering new antibacterial active ingredients and, on the other hand, developing them to market maturity, which is complex and expensive.
There are certainly ideas and initiatives for finding new antibiotics – at universities and other research institutions: A team led by Sean Brady from Rockefeller University in New York came across two novel substances using a specially developed method, which he published in 2022 in the journal “Nature ” and “Science”. His approach uses the fact that more and more bacterial genetic material has been decoded – including genes for antibacterial agents.
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.
Now the group concentrated on groups of genes for previously unknown lipopeptides. It is hoped that substances with new mechanisms of action will be found here. Ultimately, the substance cilagicin proved effective in the laboratory against all representatives of a specific group of bacteria – including resistant enterococci or resistant variants of the dreaded wound germ Staphylococcus aureus. Whether such substances – which are often toxic to the kidneys or liver, for example – are also suitable for use in humans cannot be answered at present.
Martin Grininger from the University of Frankfurt is also looking for new antibacterial agents. In the journal “Nature Chemistry”, he and his US colleagues recently presented a process for equipping antibiotics – but also other active substances – with fluorine atoms and thus specifically changing pharmacological properties – such as binding to a target molecule, stability, availability in the body and Effectiveness. In the study – carried out on the antibiotic erythromycin – the feasibility of the approach was proven, pharmaceutical tests are still pending. “We assume that the fluorine modification makes medical sense,” says Grininger.
In the fight against bacterial pathogens, there are other approaches in addition to antibiotics: New vaccinations could help, and research is being carried out into mRNA vaccines against tuberculosis, among other things. Hopes also rest on monoclonal antibodies that neutralize certain bacteria. And bacteriophages are rediscovered – i.e. viruses that multiply in bacteria until they cause the bacterial cell to burst.
Back to antibiotics: there are many new ideas and approaches at universities and other institutions as to how new active substances can be developed. But who should bring newly discovered substances 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 great risks – for example in the event of failed approval – special 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 approach the problem strategically, Müller suggests bringing all those 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 will not be on the market for at least ten years.”
