“Unlike antibiotics, where you can evolve resistance pretty quickly,” these protective molecules “don’t actually kill the bacteria. They just seem to shut off gene expression of its virulence toxins, so it’s another way that one could try to treat these infections.” 

Researchers at MIT have found molecules in mucus that can stop cholera by messing with the genes that make the microbe change into a harmful state.

These protective molecules, called glycans, are a big part of mucins, which are polymers that form a gel and make up most of mucus. The team from MIT found a type of glycan that stops Vibrio cholerae from making the toxin that usually causes severe diarrhea.

If these glycans could be sent to the site of infection, they could help to strengthen the mucus barrier and stop cholera symptoms, which affect up to 4 million people every year. According to the researchers, glycans might be a viable substitute for antibiotics since they disarm bacteria without really killing them.

“Unlike antibiotics, where you can evolve resistance pretty quickly, these glycans don’t actually kill the bacteria,” says lead author Benjamin Wang, adding, “they just seem to shut off gene expression of its virulence toxins, so it’s another way that one could try to treat these infections.”

Controlling microbes

Recent research by Ribbeck and colleagues has shown that the mucus that coats most of the body’s surfaces is crucial in regulating microbial populations. Glycans, which are complex sugar compounds present in mucus, have been shown by Ribbeck’s team to be able to inhibit the growth of yeast Candida albicans and dangerous bacteria like Pseudomonas aeruginosa.

While the majority of Ribbeck’s prior research has been on lung infections, in the latest study, the researchers’ attention has been drawn to a bacteria that infects the gastrointestinal system. Vibrio cholerae, which is often transmitted through polluted drinking water, may result in very severe diarrhea and dehydration. There are several types of Vibrio cholerae, and prior studies have revealed that the bacterium only develops pathogenicity when it is infected by the virus known as CTX phage.

Wang explains that the phage “carries the genes that encode the cholera toxin, which is really what’s responsible the symptoms of severe cholera infection.”

This “toxigenic conversion” requires the CTX phage to attach to the toxin co-regulated pilus (TCP), a receptor on the bacterial surface. Working with mucin glycans that were cleaned up from the pig’s gut, the MIT team found that glycans stop the bacteria from making the TCP receptor, which means that the CTX phage can’t infect it.

The study’s findings also revealed that mucin glycan exposure significantly changes the expression of a wide range of other genes, including those needed to make the cholera toxin. The bacteria generated practically little cholera toxin when they were in contact with these glycans.

When Vibrio cholerae gets into the epithelial cells that line the GI tract, they make too much of a molecule called cyclic AMP. They release a great deal of water as a result, which produces terrible diarrhea. The scientists discovered that when human epithelial cells were exposed to Vibrio cholerae that had been neutralized by mucin glycans, the cells did not release cyclic AMP or begin to leak water.

Glycan delivery

Then, the researchers looked into which glycans might have an effect on Vibrio cholerae. In order to do this, they collaborated with Hevey’s lab to produce synthetic copies of the glycans that were most prevalent in the naturally occurring mucin samples they were researching. The majority of the glycans they created had core 1 or core 2 structures, which vary significantly in terms of the quantity and kind of monosaccharides they contain.

According to the study, core 2 glycans were most important in controlling cholera infection. Since 50 to 60 percent of Vibrio cholerae infections are thought to be asymptomatic, the researchers propose that the absence of these cholera-blocking mucins may be the cause of symptomatic cases.

“Our findings suggest that maybe infections occur when the mucus barrier is compromised and is lacking this particular glycan structure,” Ribbeck adds.

She is now trying to find ways to send synthetic mucin glycans to infection sites, possibly along with antibiotics. Glycans can’t stick to the mucosal linings of the body on their own, so Ribbeck’s lab is looking into the possibility of attaching the glycans to polymers or nanoparticles to help them stick to those linings. The researchers plan to start with pathogens in the lungs, but they also want to use this method on pathogens in the gut, like Vibrio cholerae.

“We want to learn how to deliver glycans by themselves, but also in conjunction with antibiotics, where you might need a two-pronged approach. That’s our main goal now because we see so many pathogens are affected by different glycan structures,” Ribbeck adds.

Source: MIT