Antibiotic-free Helicobacter therapy based on innovative treatment strategies and novel drug delivery technologies

Helicobacter pylori is one of the main causes of gastritis, gastroduodenal ulcers, atrophic gastritis, gastric adenocarcinomas, and mucosa-associated lymphomas. In Germany, approximately 19,000 people are diagnosed with stomach cancer each year, while the global incidence is estimated at over 900,000 cases annually. The primary cause is infection with H. pylori.

Although effective antibiotics are available, increasing antibiotic resistance complicates successful treatment. By 2050, it is expected that annual deaths due to antimicrobial resistance (AMR) will surpass deaths from cancer (fewer than 10 million per year).

Therefore, it is of utmost importance to develop innovative therapies that do not rely on antibiotics. With the call for “Targeted Drug Delivery,” the German Federal Ministry of Education and Research (BMBF) aimed to promote precisely such new approaches, focusing on the targeted delivery of advanced therapeutics using genetically modified bacteria and/or bacteriophages.

In the HeliTec project, the concept of a new antibiotic-free treatment method was explored, which is intended to enable the direct elimination of the bacterium in the gastric mucosa. To achieve this, genetically modified, harmless Helicobacter bacteria were to be created as a drug delivery system. These act as “Trojan horses” and can produce lethal substances in close proximity to the pathogenic Helicobacter strains. The release of these substances is triggered by communication molecules emitted by the pathogenic bacteria. Three strategies were pursued in the project:

1. Release of bactericidal proteins or peptides by the Trojan bacteria.

2. Loading the Trojan bacteria with bacteriophages—viruses that attack bacteria and specifically kill pathogenic Helicobacter strains.

3. A combined approach, in which the phages are incorporated into the Trojan bacteria and are only released in the presence of pathogenic Helicobacter.

The targeted release at the site of infection is intended to enable efficient treatment. The research project thus contributes to overcoming the disadvantages of current drug delivery methods.

Fraunhofer IME’s role in this ambitious project included the genetic modification to generate an apathogenic H. pylori Trojan bacterium and the identification of suitable antimicrobial peptides for subsequent therapy. Furthermore, initial concepts were developed for integrating an expression system that could be induced by H. pylori-produced signaling molecules, thus providing the desired characteristics for targeted drug delivery. This included the development and application of autoinducer-inducible genetic elements as trigger mechanisms using quorum-sensing signals. Fraunhofer IME also participated in initial in vitro experimental tests to examine and validate the effects of the developed Trojan bacteria.