Motility inhibitors as novel therapeutic approach against common intestinal pathogens

Short description

Helicobacter pylori, Campylobacter jejuni, and Campylobacter coli are among the most widespread bacterial pathogens and responsible for annually hundreds of thousands of cases of diarrhoea, intestinal inflammation, gastric ulcers and stomach cancer worldwide. The research group led by Christine Josenhans at the Ludwig-Maximilians-Universität München (LMU) is developing pathoblockers that are able to inhibit the bacteria's locomotion and navigation abilities and thereby their proliferation and pathogenic activity.

Helicobacter pylori is an important chronic bacterial pathogen of the human stomach. In previous DZIF projects, pathoblockers against H. pylori were developed that are able to inhibit bacterial motility. The therapeutic principle is based on the inhibition of the motility mediated by flagella—hair-like appendages found on various bacterial species that propel and manoeuver the cells and contribute to their pathogenicity. For one of the substances, the team was able to observe a strong reduction in bacterial proliferation in the stomach of mice infected with H. pylori, without significantly damaging the normal bacterial intestinal flora. “This would be a great advantage over conventional antibiotics, which also oftentimes permanently attack the essential ‘good’ intestinal bacteria”, explains Prof. Josenhans, the senior author of the study. Based on successful testing, a patent including specific H. pylori pathoblockers (antimotilins) has recently been filed.

The bacterial class Proteobacteria, which includes Helicobacter spp., also includes members of the Campylobacter genus, such as some of the world's most important representatives of foodborne diarrhoeal pathogens, Campylobacter jejuni and C. coli. Some Campylobacter variants can infect the intestinal tract of both livestock and humans and can be transmitted from animals to humans. In animals, they often cause little symptoms even in the case of chronic infestation, whereas in infected humans they can lead to acute as well as chronic inflammatory intestinal diseases.

Antibiotic resistance is currently increasing rapidly among these diarrhoeal pathogens, which has led to their inclusion on the WHO list of 12 bacterial families that pose the greatest threat to human health. Campylobacter species are likely to acquire most antibiotic resistance already during food production and through animal hosts in livestock, with the resistant bacteria then being transmitted to humans. New antibacterial approaches against these intestinal pathogens—especially Campylobacter ssp.— in both livestock and humans are therefore urgently needed.

Since bacterial motility is essential for the survival of these pathogens in their hosts, inhibition of motility in vivo represents a promising strategy. The focus of this project is therefore to better understand and apply the newly developed anti-virulence principles of motility inhibition, already established in H. pylori, in the control of other important antibiotic-resistant bacterial pathogens. In this context, motility inhibition and other antibacterial effects of small substances as well as inhibition of specific bacterial proteins with known compounds will be investigated. In parallel, the approach of H. pylori motility inhibition will be pursued with the aim of an approved patent and marketable therapeutic application based on the recent patent application.