Hope for preventing stomach cancer
New drug candidate extremely effective against H. pylori bacterium
Approximately 43 percent of the world’s population is infected with this bacterium. It can cause chronic inflammation of the stomach lining, lead to gastric ulcers, and is considered a key risk factor for stomach cancer. Standard therapies are primarily based on the antibiotic metronidazole. However, H. pylori is becoming increasingly resistant to it. As a result, ever higher doses and combinations with additional antibiotics are required.
The team led by Prof. Stephan A. Sieber, Chair of Organic Chemistry II at the TUM School of Natural Sciences, examined the antibiotic’s mechanisms of action in detail. It was already known that metronidazole induces so-called “oxidative stress” in the bacterium, meaning chemical reactions that damage cellular components. The researchers have now discovered that metronidazole additionally targets two central protective proteins of H. pylori: an enzyme responsible for detoxifying harmful reactive oxygen species and a protein that repairs damaged proteins.
The study’s first authors, Dr. Michaela Fiedler and doctoral researcher Marianne Pandler, both at the Chair of Organic Chemistry II, explain: “Based on our new fundamental insights, we developed chemically slightly modified variants of metronidazole, known as ether derivatives. This molecular optimization enables the drug to bind more effectively to its target proteins. As a result, H. pylori is less able to counteract oxidative stress and, in the best case, is eliminated.”
In laboratory experiments, the researchers observed up to a 60-fold increase in efficacy against standard H. pylori strains, as well as strong activity against already resistant bacterial strains. At the same time, they found no increased toxicity of the modified compound toward human cells.
In mice, the team was able to completely eradicate H. pylori infection using the new compound, already at a very low dose. Moreover, the gut microbiome of the mice was less affected than with current standard therapy.
Prof. Stephan A. Sieber emphasizes: “We have developed a highly promising potential drug candidate to reduce the risk of stomach cancer. However, the results still need to be confirmed in clinical trials in humans. If successful, this would represent a genuine medical breakthrough.”
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The team led by Prof. Stephan A. Sieber, Chair of Organic Chemistry II at the TUM School of Natural Sciences, examined the antibiotic’s mechanisms of action in detail. It was already known that metronidazole induces so-called “oxidative stress” in the bacterium, meaning chemical reactions that damage cellular components. The researchers have now discovered that metronidazole additionally targets two central protective proteins of H. pylori: an enzyme responsible for detoxifying harmful reactive oxygen species and a protein that repairs damaged proteins.
The study’s first authors, Dr. Michaela Fiedler and doctoral researcher Marianne Pandler, both at the Chair of Organic Chemistry II, explain: “Based on our new fundamental insights, we developed chemically slightly modified variants of metronidazole, known as ether derivatives. This molecular optimization enables the drug to bind more effectively to its target proteins. As a result, H. pylori is less able to counteract oxidative stress and, in the best case, is eliminated.”
In laboratory experiments, the researchers observed up to a 60-fold increase in efficacy against standard H. pylori strains, as well as strong activity against already resistant bacterial strains. At the same time, they found no increased toxicity of the modified compound toward human cells.
In mice, the team was able to completely eradicate H. pylori infection using the new compound, already at a very low dose. Moreover, the gut microbiome of the mice was less affected than with current standard therapy.
Prof. Stephan A. Sieber emphasizes: “We have developed a highly promising potential drug candidate to reduce the risk of stomach cancer. However, the results still need to be confirmed in clinical trials in humans. If successful, this would represent a genuine medical breakthrough.”
END