Compounds from the human gut microbiome could fight drug-resistant bacteria

The human gut is home to about 100 trillion microbes living side by side, competing for limited resources. To survive, they may have to get creative. Scientists at the University of Pennsylvania (UPenn) and Stanford University hypothesized that some of the innovative ways gut microbes outcompete the competition could be used as antibiotics. They explored this idea in a new paper published in cell entitled “Study of human microbiomes reveals an untapped source of peptide antibiotics.”

In the search for effective treatments against drug-resistant bacteria, scientists in the lab of César de la Fuente, PhD, an assistant professor of bioengineering and chemical and biomolecular engineering at UPenn, have searched for antibiotic candidates from a variety of sources, including the genetic information of extinct creatures such as Neanderthals and woolly mammoths, as well as mass samples of bacteria analyzed using artificial intelligence. For this study, they collaborated with scientists in the lab of Ami Bhatt, MD, a professor of medicine (hematology) and genetics at Stanford.

“One of our main goals is to use the world's biological information as a source of antibiotics and other useful molecules,” said de la Fuente. “Instead of relying on traditional, laborious methods that require collecting soil or water samples and purifying active compounds, we leverage the enormous amount of biological data found in genomes, metagenomes and proteomes. This allows us to discover new antibiotics at digital speed.”

Using computational tools, the scientists examined gut microbiome data from nearly 2,000 people. Their analysis of over 400,000 proteins from the study participants revealed dozens of potential peptide antibiotics. They selected 78 and synthesized them to test on bacterial cultures as well as animal models. Over half of the peptides tested inhibited bacterial growth of both friendly and pathogenic bacteria. The leading candidates from these tests proved to be “anti-infective” in both mouse models of skin abscesses and models of deep thigh infections. In particular, prevotellin-2 from Cooked Prevotella showed activity comparable to the commonly used antibiotic polymyxin B,” the researchers wrote.

“Interestingly, these molecules have a different composition than what is traditionally considered antimicrobial,” said Marcelo Torres, a research associate in the de la Fuente lab and first author of the study. “The compounds we discovered form a new class and their unique properties will help us understand and expand the sequence space of antimicrobials.”

In addition, “the discovery of prevotellin-2, whose effects are comparable to those of one of our last antibiotics, polymyxin B, was a great surprise to me,” Bhatt said. “This suggests that exploring the human microbiome for new and exciting classes of antimicrobial peptides is a promising avenue for researchers and physicians, and most importantly, for patients.”