Targeting Helicobacter: nipping stomach cancer in the bud
The pathogen Helicobacter pylori, which is responsible for highly prevalent diseases such as gastric ulcers or cancer, has a weak spot that could be used to produce new drugs. This was discovered by a group of researchers led by DZIF scientist Prof. Rainer Haas and biologist Dr. Wolfgang Fischer from the Max von Pettenkofer Institute of Hygiene and Medical Microbiology at the Ludwig-Maximilians-Universität Munich. Their results have now been published in the journal Cell Chemical Biology.
More than four billion people worldwide are infected with the stomach pathogen H. pylori, leading to over 800,000 cases of stomach cancer every year. Because the bacterium is becoming increasingly resistant to current drugs, the World Health Organisation (WHO) has classified it as a high-priority pathogen for research and development of new antibiotics. New approaches and therapeutics are urgently needed to replace or complement established treatments.
The new study, which was carried out in cooperation with the German Center for Infection Research (DZIF) and other partners, has now taken a major step in this direction. “We were able to demonstrate that the bacteria are highly sensitive to certain substances that inhibit cellular respiration,” says Haas.
Fighting helicobacter and protecting the gut microbiome
The researchers were able to identify several compounds from various substance groups that paralyse the respiratory chain of H. pylori even in low concentrations. For other beneficial bacteria, including representatives of the normal gut microbiome, these substances are unproblematic because these bacteria tolerate larger amounts of them.
The authors of the study used a wide range of biochemical and microbiological methods as well as molecular modeling techniques to find out why H. pylori reacts so sensitively to these substance groups. The cause is a slightly altered structure of the so-called quinone-binding pocket in respiratory complex I.
This Achilles' heel offers great potential for the development of new tailored active agents that could be used as pathogen blockers against H. pylori. "Our results reveal a surprising weakness in the metabolism of these bacteria, which are otherwise well adapted to their unusual environment," says Fischer.
The LMU research team was also able to identify possible mutations that make bacteria less sensitive to the inhibitors. However, these mutations also weaken the metabolism. Thus, less resistance to the complex I inhibitors is formed.
"Overall, our results are very promising," adds Haas. "We managed to identify a whole group of inhibitors that do not show cross-resistance with current therapeutics. They are not very susceptible to resistance development and have little impact on the gut microbiome."
