The dangerous salmonella bacteria have often developed resistance mechanisms to antibiotics that inhibit the growth of bacteria or kill them. Alternative treatment options are therefore urgently needed. Pathoblockers are one such alternative. The discovered substance acts at an early stage, before the bacteria penetrate the tissue, by specifically disrupting the pathogen’s infection mechanisms. As drugs, they have a very specific and targeted effect against salmonella. According to current knowledge, the probability of salmonella acquiring resistance to these substances from other bacteria is likely to be significantly lower," says Samuel Wagner.
Targeting a central regulator
When attacking their target tissue in the gastrointestinal tract, Salmonella set secretion systems in motion that are based on several transcription regulators, "One of these regulators, HilD, plays a central role in the penetration of Salmonella into the host cell. We have identified a suitable target structure at HilD for new drug candidates," says Abdelhakim Boudrioua from the Cluster of Excellence CMFI, the first author of the study. In order to transmit the signals for protein production, the regulators must bind highly specifically to other regulators and DNA and trigger further reactions. The binding site at HilD can be imagined on a molecular level as a detailed three-dimensional pocket. The discovered substance fits exactly into this pocket and thus disrupts the function of the regulator, explains the researcher. This could stop the infection process.The research team searched large substance databases for potential candidates. "We identified C26 as the most promising substance. We then carried out a comprehensive analysis of the mode of action and the exact binding site on the structure of HilD," says Boudrioua. This was followed by numerous tests on the efficiency of C26 in suppressing the infection, for example by demonstrating that the inhibitor impairs the pathogenicity of bacteria hiding in macrophages - the cells of the host’s immune system. "According to our results, C26 was able to stop the Salmonella infection process at the central regulator HilD at an early stage. It appears to act specifically on the pathogens and has no further effect on the beneficial human microbiome," summarizes Wagner. "We now have a suitable starting material for further development as a drug."
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. (Doshisha) Karla Pollmann, Rector of the University of Tübingen.
There is still a long way to go before a new therapy against salmonella infections with pathoblockers such as HilD Regulators is available, says Wagner. In addition to humans, drugs could also be developed for animals, especially poultry. The efforts could be worthwhile: Unlike antibiotics, which in many cases also damage patients’ beneficial intestinal bacteria, specific pathoblockers are not expected to have any negative effects on the body and its own microbiome, he says.
