Novel Compound Targets Salmonella's Infection Mechanism

Pathogenic Salmonella strains invade the gastrointestinal tract by injecting effector proteins into host cells, allowing the bacteria to infiltrate and multiply. Infections typically occur after consuming contaminated food and can lead to severe gastrointestinal inflammation or even systemic illness.

Now, a multinational team of researchers from the German Center for Infection Research (DZIF) and the University of Tübingen’s Cluster of Excellence "Controlling Microbes to Fight Infections" (CMFI), led by Professor Samuel Wagner, has identified a compound that disrupts this infection process at an early stage.

The synthetic compound, known as C26, prevents the injection of effector proteins—an essential step in the infection mechanism. According to findings published in Science Advances, C26 could be developed into a treatment for both human and animal Salmonella infections.

Given that Salmonella has developed resistance to many conventional antibiotics, there’s a growing need for alternative therapeutic strategies. One such approach involves pathoblockers—substances that don’t kill bacteria outright but instead interfere with their ability to cause disease. C26 appears to act early in the infection cycle, blocking the bacteria before they can penetrate tissue.

“As a potential drug, C26 has a highly targeted effect on Salmonella,” said Professor Wagner. “Based on what we know so far, it’s also unlikely that Salmonella will easily develop resistance to it through mechanisms shared with other bacteria.”

Targeting a Key Regulator

When Salmonella invades the gastrointestinal tract, it activates specialized secretion systems controlled by numerous transcriptional regulators. Among them, a protein called HilD plays a pivotal role in enabling bacterial entry into host cells.

“We found that HilD contains a specific structural feature—a pocket—that can be targeted by drug-like compounds,” explained Dr. Abdelhakim Boudrioua, the study’s first author. “This gave us a way to search for molecules that could disrupt its function.”

For protein synthesis signals to be sent, regulators like HilD must bind precisely to other regulators and to DNA. The pocket identified in HilD is a complex, three-dimensional cavity that the researchers were able to exploit.

“The compounds we discovered fit snugly into this pocket, blocking the regulator’s activity and effectively halting the infection process,” said Boudrioua.

Using large-scale screening, the team evaluated thousands of potential compounds before identifying C26 as a standout candidate. They then conducted detailed analyses of how it binds to HilD and disrupts its function.

Follow-up experiments confirmed that C26 interferes with Salmonella's ability to infect even inside macrophages—the immune cells tasked with clearing infections.

“Our results suggest that C26 targets HilD specifically and does not disturb the beneficial bacteria in the human microbiome,” Boudrioua added. “It’s a promising lead compound for future drug development.”

From Lab to Treatment

While the findings are encouraging, Professor Wagner notes that developing HilD inhibitors like C26 into usable treatments will take time. That said, the potential applications go beyond human medicine.

“Such compounds could be especially useful in veterinary medicine, particularly in poultry farming,” Wagner said. Unlike traditional antibiotics, which can harm beneficial gut bacteria, pathoblockers like C26 appear to have no adverse effects on the body or microbiome.