New pathoblocker to stop Salmonella infection early
Research team from the University of Tübingen and the DZIF discovers substance that inhibits pathogen signaling during cell invasion.
Illustration of the HilD regulator showing the binding site for the pathoblocker C26 (blue). The structure of the HilD regulator calculated by Alpha Fold—an AI program for predicting the 3D structure of proteins—is shown in black. Model by Thales Kronenberger. 3D vizualisation by Leon Kokkoliadis, University of Tübingen.
Pathogenic strains of Salmonella inject effector proteins into the cells of the gastrointestinal tract to invade and multiply within them. The bacteria are usually ingested with contaminated food. They can cause severe gastrointestinal inflammation and even systemic infections. Now, an international team of researchers led by Professor Samuel Wagner of the University of Tübingen's 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 infection process at an early stage. The synthetic substance C26 inhibits the injection of effector proteins. It could be developed into a drug to combat Salmonella infections in humans and animals. The discovery was published in the journal Science Advances.
Salmonella bacteria have developed multiple resistance mechanisms to antibiotics that inhibit their growth or kill the bacteria. As a result, an alternative treatment is urgently needed. Pathoblockers provide such an alternative. The discovered substance acts early, before the bacteria penetrate the tissue, by specifically targeting and disrupting the infectious mechanisms of the pathogen. "As a drug, it has a very specific and targeted effect against Salmonella bacteria. As far as we know today, it is therefore much less likely that Salmonella will develop resistance to these substances from other bacteria," says Samuel 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 called HilD plays 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 very specifically to other regulators and to DNA and trigger further reactions. It turns out that HilD has a druggable pocket. On the molecular level, it can be imagined as an intricately shaped, three-dimensional pocket. "The substances discovered fit exactly into this pocket and disrupt the function of the regulator," explains the researcher. "In this way, the infection process can be stopped."
Detailed view of the HilD regulatory protein and the binding of the pathoblocker C26 (blue). The structures predicted by Alpha Fold are shown in black. Model by Thales Kronenberger. 3D visualization by Leon Kokkoliadis, University of Tübingen.
The research team screened large libraries of compounds for potential candidates. "We identified C26 as a promising compound. We then undertook an extensive analysis of its mode of action and its precise binding site on the structure of HilD," says Boudrioua. This was followed by numerous tests of C26's efficacy in disrupting infection, for example by demonstrating that the inhibitor interferes with the pathogenicity of bacteria hiding inside macrophages—the cells of the host's immune system. "According to our results, C26 could stop the process of Salmonella infection early at the central regulator HilD. It appears to have a specific effect on the pathogen and does not interfere with the beneficial human microbiome. We now have a suitable precursor for further drug development," he adds.
A long road to a drug
However, Wagner says the road to treating Salmonella infections with pathoblockers such as HilD inhibitors is long. In addition to human use, these treatments could also be developed for veterinary use, particularly in poultry. The effort could be worthwhile. In contrast to antibiotics, which also damage patients' beneficial gut bacteria in many ways, specific pathoblockers are not expected to have any negative effects on the body and its own microbiome, says Wagner.
Source: Press release of the University of Tübingen (in German)
