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New pathoblocker can stop Salmonella infections early on

Pathogenic Salmonella injects effector proteins into the cells of the gastrointestinal tract to penetrate and multiply within them. The bacteria are usually ingested with contaminated food. They can cause serious gastrointestinal inflammation and even systemic infections.

Now, an international research team led by Professor Samuel Wagner of the University of Tübingen Cluster of Excellence Controlling Microbes to Fight Infections (CMFI) and the German Center for Infection Research (DZIF) has discovered a substance that can stop the process of infection early on.

The synthetic substance C26 inhibits the injection of effector proteins, and it could be developed into a drug for combating Salmonella infections in humans and animals. The discovery has been in the journal Science Advances.

Salmonella has developed multiple resistance mechanisms to antibiotics that inhibit its growth or kill the bacteria. As a result, alternative treatment is urgently needed. Pathoblockers present such an alternative. The discovered substance acts early, before the bacteria penetrate the tissues, by specifically targeting and disrupting the infectious mechanisms of the pathogen.

"As a medication, it has a very specific and targeted effect against Salmonella. According to today's knowledge, the probability would therefore be much lower that Salmonella would acquire resistance against these substances from other bacteria," says Wagner.

Targeting the central regulator

While attacking their target tissue in the gastrointestinal tract, Salmonella set in motion secretion systems that rely on several (transcriptional) regulators.

"Among these regulators, one named HilD has a central role in the entry of Salmonella into the host cell. We were able to find a suitable target within the structure of HilD to identify new drug candidates," says Dr. Abdelhakim Boudrioua of the CMFI Cluster of Excellence and first author of the study.

In order to transmit signals for protein synthesis, the regulators must bind highly specifically to other regulators and DNA and trigger further reactions. It turns out that HilD has a druggable pocket. On a molecular level, it can be imagined as an intricately shaped, three-dimensional pocket.

The researcher explains that the discovered substances fit precisely in this pocket, and as a result, disrupt the function of the regulator. In this way, the process of infection can be stopped, he continues.

The research team screened large compound libraries for potential candidates.

"We were able to identify C26 as a promising substance. We then proceeded with an extensive analysis of its mode of action and its precise binding site on the structure of HilD," says Boudrioua.

Numerous tests of the efficiency of C26 in disrupting infection followed; for example, by proving that the inhibitor interferes with the pathogenicity of bacteria hiding inside macrophages—the cells of the immune system of the host.

"According to our results, C26 could stop the process of Salmonella infection early on at the central regulator HilD. It seems to have a specific effect on the pathogen and does not disturb the beneficial human microbiome," says Boudrioua. "We now have a suitable precursor for further drug development."

"The discovery impressively underlines how our excellent basic research at the University of Tübingen produces innovative solutions for urgent medical problems," adds Professor Dr. Dr. h.c. (Dōshisha) Karla Pollmann, President and Vice-Chancellor of the University of Tübingen.

Still, Wagner says the route to treating Salmonella infections with pathoblockers such as HilD inhibitors is long. Aside from human use, these treatments could also be developed for veterinary medicine, particularly for poultry. The efforts could be worth it. Unlike antibiotics, which also damage the patients' useful intestinal bacteria in many ways, Wagner says specific pathoblockers are not expected to have any negative effects on the body and its own microbiome.