Researchers have discovered the first known microcin, a type of natural antimicrobial, that specifically targets the bacteria responsible for cholera.
Every year, over a million individuals succumb to infections from pathogens that resist antimicrobials, and this issue is escalating. At the same time, the pace of new antimicrobial discoveries to combat these infections has not kept up.
A team from The University of Texas at Austin sees hope in a category of natural antimicrobials known as microcins. These are produced by gut bacteria, enabling them to outcompete other bacterial strains. In two recent studies, the researchers identified the first microcin that targets cholera-causing bacteria and described a technique for discovering microcins in bacterial genomes using artificial intelligence.
“Imagine a future where you could consume yogurt containing probiotic bacteria that produce microcins to help prevent or treat cholera, harmful E. coli, inflammatory bowel disease, or even colon cancer,” stated Bryan Davies, a molecular biosciences professor and a senior author on both studies. “The concept is to introduce beneficial bacteria that would continuously generate microcins in the gut to fend off specific pathogens.”
The cholera research, featured in Cell Host & Microbe, was spearheaded by Ph.D. candidate Sun-Young Kim at UT.
Cholera, a severe diarrheal illness caused by the Vibrio cholerae bacteria, can lead to rapid dehydration and may be fatal within hours. According to the World Health Organization, cholera accounts for approximately 21,000 to 143,000 deaths globally each year. Another type of gut bacteria is believed to trigger inflammatory bowel disease flare-ups, while yet another is linked to colon cancer progression. Each of these conditions could potentially be targeted by microcins.
Microcins are very specific in their action, typically attacking particular bacteria, unlike traditional antibiotics that can kill both harmful and beneficial bacteria indiscriminately. This selectivity means microcins have the potential to eliminate unwanted bacteria without disrupting the delicate balance of the gut microbiome, which is essential for overall health. Additionally, because their mode of action differs from that of traditional antibiotics, they could remain effective against bacteria that have developed resistance.
Finding microcins within a bacterium’s genome is challenging due to the short and varied nature of their genetic sequences. To overcome this, the team searched the V. cholerae genomes for a larger protein called PCAT, associated with microcins and responsible for exporting them from the producing bacteria to target others. It’s similar to using a familiar landmark to guide friends to your home (“I’m just two doors down from the fire station.”).
The researchers identified around two dozen candidate microcins from non-pathogenic strains of V. cholerae. They demonstrated that one of these, named MvcC, can kill pathogenic strains of V. cholerae. Essentially, it serves as a natural strategy for one bacterial strain to outcompete its relatives.
“There are already bacteria in your gut producing microcins,” Davies remarked. “They are a natural component of how bacterial communities organize and interact.”
So how do the V. cholerae strains that produce microcins avoid damaging themselves?
Researchers discovered that these microcin-producing V. cholerae strains also create a protective substance known as an immunity protease. They showed that, in mice infected with both pathogenic and non-pathogenic strains of V. cholerae, the bacteria expressing microcins had a competitive advantage over those without.
The researchers aim to advance their cholera-related work in three main directions:
- Modifying the anti-Vibrio microcin MvcC to enhance its lethality against V. cholerae and improve its stability within the human body.
- Creating combinations of various anti-Vibrio microcins to avert the emergence of antimicrobial resistance.
- Identifying which microcin-producing bacterial strains are most effective at generating and delivering microcins to gut pathogens.
In a related upcoming paper, soon to be published in a peer-reviewed journal and available as a preprint, the scientists outline a new AI-driven method for identifying additional microcin candidates. This method utilizes protein LLMs—biological equivalents to the generative AI models behind chatbots like ChatGPT—to identify sequences resembling known microcins. This represents one of several AI-based methods the team is trying out, hoping to facilitate further microcin discoveries.
“Microcin biology is quite distinctive and significantly underexplored,” commented Claus Wilke, a professor of integrative biology and statistics at UT and a co-author of the forthcoming paper. “This makes it an exciting area of research with immense potential for new findings.”
This research has been supported by The Welch Foundation, the National Institutes of Health, the U.S. Army Research Office, the Winkler Family Foundation, and Tito’s Handmade Vodka.
