Pathogenic bacteria are getting deadlier because they are increasingly gaining resistance to crucial antibiotics. Whole scientists are trying to create new antibiotics, doing so can take a lot of effort and time before they have been sufficiently validated and tested. Researchers have now learned more about the mechanisms used by a type of infectious Salmonella that can cause inflammatory diarrhea. This work also identified a molecule that can help stop these processes, and which may lead to better treatments for these serious infections. The findings have been reported in Science Advances.
In recent years, scientists have expanded the search for drugs that can stop infections. While antibiotics aim to stop bacterial cells from growing, or kill them, a different class of drugs aims to stop the processes they use in a host, to halt the process of infection. These drugs that aim to interfere with how a pathogen interacts with its host, are known as pathoblockers. Once a pathoblocker halts the mechanisms of a pathogen, the host's defenses are free to attack, disable, and eliminate the infection.
When pathogenic Salmonella are ingested, usually in contaminated food, the bacteria can use its specialized secretion systems to inject bacterial proteins into target gastrointestinal cells. These infections and bacterial proteins can lead to severe gut inflammation and sometimes, more serious infections that affect the whole body.
This study showed that a synthetic molecule called C26 can stop bacteria from secreting effector proteins into host cells. The molecule, which is a kind of pathoblocker, could halt infections quickly and may help reduce the number of Salmonella infections in people and animals. Pathoblockers work specifically to halt the pathogenicity or infectiousness of a microbe; in this case, a subspecies of Salmonella enterica known as enterica serovar Typhimurium.
"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," explained corresponding study author Professor Samuel Wagner of the University of Tübingen Cluster of Excellence Controlling Microbes to Fight Infections (CMFI), among other appointments.
The secretion systems of Salmonella work with molecules that control gene expression on a wide scale – transcriptional regulators. One in particular called HilD is crucial to Salmonella's entry into host cells, noted first study author Dr. Abdelhakim Boudrioua of the CMFI Cluster of Excellence. "We were able to find a suitable target within the structure of HilD to identify new drug candidates."
Transcriptional regulators typically bind in a very specific way to DNA or other molecules to control gene expression. This specificity could be explored with HilD, which carries a target pocket for a drug.
The researchers identified compounds that could fit into this pocket precisely, which interfered with the process of transcriptional regulation. As such, the process of infection was halted.
The investigators confirmed the efficacy of C26 by testing it in a variety of infection models.
"We now have a suitable precursor for further drug development," said Boudrioua.
While this is an excellent candidate, Wagner noted that pathoblockers won't be ready for use in the clinic for awhile. However, they may be available for use in animals a bit sooner. Even so, a lengthy testing and validation period may be worth it, since pathoblockers are not expected to have detrimental effects on humans cells or the human gut microbiome, added Wagner.
Sources: University of Tübingen, Science Advances