2023-04-25 10:26:00
“Infection with the bacterial pathogen Clostridioides difficile can lead to severe diarrheal diseases in humans and animals. This is particularly the case when the natural microbiome of the gut is disrupted, for example by previous treatment with a broad-spectrum antibiotic,” says Prof. Till Strowig, head of the “Microbial Immune Regulation” department at the HZI. “Then C. difficile finds ideal conditions in the intestine and can multiply unhindered – which leads to severe diarrhea and intestinal inflammation, which can also become chronic.” at a later point in time – when the conditions are favorable for him – can lead to an infection again. Since the C. difficile infection also has to be treated with antibiotics and the intestinal microbiome cannot recover, a real vicious circle is created. Up to 25 percent of those who become ill for the first time later develop further infections with C. difficile. About ten percent of the patients who fall ill again die as a result of the reinfection. According to the Infection Protection Act, an infection with C. difficile must be reported to the health department. The pathogen is transmitted via contact infections.
“Unfortunately, the antibiotics that are commonly used today to treat a C. difficile infection are not as effective and lasting as one would like. Our study addresses this problem,” says Strowig, who headed the large-scale, multidisciplinary collaborative study together with Prof. Thilo Fuchs, deputy head of the Institute for Molecular Pathogenesis at the FLI. “We wanted to find out whether and to what extent the natural substance chlorotonil A – it is obtained from a soil bacterium – is effective against C. difficile and how it also influences the microbiome of the intestine,” says Fuchs.
At HIPS, intensive research has been carried out on chlorotonil A (ChA) and its chemical variants for more than ten years in order to improve them as potential active pharmaceutical ingredients and to optimize them for possible future use in humans. Against the background of increasing resistance, the development of new antibiotic agents is urgently needed – and the researchers see the chlorotonil variants as promising drug candidates. “ChA has a broad spectrum of antibiotic activity against gram-positive bacteria and, for example, effectively combats the hospital germ Staphylococcus aureus, also known as MRSA. In addition, ChA is also effective against the malaria pathogen,” says Prof. Rolf Müller, Executive Director of HIPS and head of the “Microbial Natural Products” department at HIPS and coordinator of the “New Antibiotics” department at the German Center for Infection Research (DZIF). “For our study, we entered the two drug candidates ChA and Chlorotonil B1-Epo2 into the running. We were interested in how their effectiveness compares to that of the antibiotic vancomycin, which is often used in infections with C. difficile.” For their investigations, the research team used a wide range of methods and brought together the expertise of all research institutions involved. Microbiological methods, animal models and the latest molecular biological methods (multi-omics) were used. “The multidisciplinary approach of our study was crucial for the fact that we were able to achieve such comprehensive and extremely satisfactory results,” says Strowig, who also conducts research at the DZIF in the field of “Emerging infectious diseases”. His colleague Fuchs adds: “A special feature of our study was the complementary integration of all data into a model that can facilitate the control of zoonotic diseases.”
In microbiological studies, the researchers found that the two chlorotonil variants were as effective against C. difficile as vancomycin. ChA proved to be just as effective in the mouse model. “In the series of experiments with the mice, the antibiotics were discontinued after a while – and then the surprise effect occurred,” says Arne Bublitz, doctoral student in the “Microbial Immunology” department at the HZI and first author of the study. “The majority of mice previously treated with vancomycin became ill again. In contrast, none of the mice treated with ChA had a reinfection.” What exactly was behind this? Bublitz investigated this question in further microbiological investigations. He treated resting stages of C. difficile with ChA and then tried to bring them back to life by creating the ideal conditions for the bacterium. But it didn’t work: no viable bacterial cells developed from the treated spores. And the disease was also significantly attenuated in mice infected with ChA-treated remnants. “By washing with solvents, we were able to find out that the active ingredient ChA is most likely stored in the water-repellent shell of the permanent stages and forms a kind of active ingredient depot there,” explains Bublitz. “If the cell begins to germinate, it comes into contact with the stored ChA and dies. ChA is one of the first examples of an antibiotic that can effectively target both bacterial cells and persistent stages in vivo at low effective concentrations.”
Another research focus of the study was the effects of ChA on the microbiome. To this end, a research team from the FLI carried out studies on pigs – whose digestive system is very similar to that of humans. “Using a wide range of multi-omics methods, we were able to show that ChA causes significantly less damage to the pig microbiome than other antibiotics,” says Fuchs. “Furthermore, ChA had a clearly negative effect on the gene regulation of the intestinal pathogen.” Strowig adds: “And we also came to positive results in the mouse model: After administration of ChA, the microbiome of the intestine recovered faster than it did with the administration of other antibiotics case was. ChA therefore appears to have a very specific effect and only slightly disturbs the microbiome in terms of its protective function.” Both scientists emphasize that the active substance ChA increases the concentration of intestinal metabolites such as proline or short-chain fatty acids, which promote the growth of C. difficile , not changed – unlike this is the case with conventional antibiotics.
The results of the study clearly show that chlorotonil variants are promising drug candidates for the treatment of C. difficile infections. “In particular, the effect of ChA on the long-term stages that lead to renewed outbreaks of the disease could represent a milestone in the treatment of C. difficile infections,” says Strowig. “We hope that with our study we will contribute to further advancing drug research based on natural substances in order to identify new effective active ingredients for combating infectious diseases. Because they may be able to attack the target structures of the pathogens that were previously inaccessible with known means.”
About the study:
The study was funded by the German Center for Infection Research (DZIF) and the Federal Ministry of Education and Research (BMBF; Consortium InfectControl 2020). More about InfectControl 2020: https://www.innovation-strukturwandel.de/strukturwandel/de/unternehmen-region/die-initiativen/_documents/artikel/io/infectcontrol-2020.html
Originalpublikation:
Arne Bublitz, Madita Brauer, Stefanie Wagner, Walter Hofer, Mathias Müsken, Felix Deschner, Till R. Lesker, Meina Neumann-Schaal, Lena-Sophie Paul, Ulrich Nübel, Jürgen Bartel, Andreas M. Kany, Daniela Zühlke, Steffen Bernecker, Rolf Jansen, Susanne Sievers, Katharina Riedel, Jennifer Herrmann, Rolf Müller, Thilo M. Fuchs, Till Strowig: The natural product chlorotonil A preserves colonization resistance and prevents relapsing Clostridioides difficile infection. Cell Host & Microbe, 2023, https://doi.org/10.1016/j.chom.2023.04.003.
Helmholtz Institute for Pharmaceutical Research Saarland:
The Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) in Saarbrücken was founded in 2009 by the HZI and Saarland University. In particular, the researchers are looking for new active substances against infectious diseases, optimizing them for use in humans and researching how these can best be transported to their site of action in the human body. www.helmholtz-hzi.de/hips
German Center for Infection Research:
At the German Center for Infection Research (DZIF), more than 500 scientists from 35 institutions nationwide are jointly developing new approaches for the prevention, diagnosis and treatment of infectious diseases. The aim is what is known as translation: the fast, effective implementation of research results in clinical practice. The DZIF is thus paving the way for the development of new vaccines, diagnostics and drugs against infections. You can find more information at www.dzif.de.
Friedrich-Loeffler-Institut:
As the Federal Research Institute for Animal Health, the Friedrich Loeffler Institute (FLI) is dedicated to the health of food-producing animals. Central tasks are the prevention, diagnosis and control of animal diseases, the improvement of animal husbandry and nutrition as well as the conservation and use of animal genetic resources. The Institute for Molecular Pathogenesis (IMP) at the Jena site represents the competence of the Friedrich Loeffler Institute in researching bacterial pathogens. www.fli.de
Leibniz-Institute DSMZ:
The Leibniz Institute DSMZ – German Collection of Microorganisms and Cell Cultures GmbH is the world’s most diverse collection of biological resources (bacteria, archaea, protists, yeasts, fungi, bacteriophages, plant viruses, genomic bacterial DNA and human and animal cell cultures). Microorganisms and cell cultures are collected, researched and archived at the DSMZ. As an institution of the Leibniz Association, the DSMZ with its extensive scientific services and biological resources has been a global partner for research, science and industry since 1969. The DSMZ is recognized as a non-profit organization, the first registered collection in Europe (Regulation (EU) No. 511/2014) and certified according to the ISO 9001:2015 quality standard. As a patent depository, it offers the only nationwide opportunity to deposit biological material in accordance with the requirements of the Budapest Treaty. In addition to the scientific service, research is the second mainstay of the DSMZ. The institute, based on the Science Campus Braunschweig-Süd, houses more than 83,000 cultures and biomaterials and has around 220 employees. www.dsmz.de
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