Roughly 100 trillion microbes coexist and compete for limited resources in the human gut. 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 that gut microbes use to beat out the competition could have potential use as antibiotics. They explored this idea in a new paper published in Cell titled, “Mining human microbiomes reveals an untapped source of peptide antibiotics.”
In the search for effective treatments against drug-resistant bacteria, scientists in the laboratory of César de la Fuente, PhD, an assistant professor in bioengineering and chemical and biomolecular engineering at UPenn, have hunted for antibiotic candidates from a range of sources including the genetic information of extinct creatures like Neanderthals and wooly mammoths to masses of bacteria analyzed using artificial intelligence. For this study, they worked with scientists in the lab of Ami Bhatt, MD, a professor in medicine (hematology) and genetics at Stanford.
“One of our primary goals is to mine the world’s biological information as a source of antibiotics and other useful molecules,” de la Fuente said. “Rather than relying on traditional, painstaking methods that involve collecting soil or water samples and purifying active compounds, we harness the vast array of biological data found in genomes, metagenomes, and proteomes. This allows us to uncover new antibiotics at digital speed.”
Using computational tools, the scientists surveyed the 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 and synthesized 78 to test against bacterial cultures as well as animal models. Over half of the peptides tested inhibited bacterial growth of either friendly or pathogenic bacteria. The lead candidates from these tests proved to be “anti-infective in both murine skin abscess and deep thigh infection models. Notably, prevotellin-2 from Prevotella copri presented activity comparable to the commonly used antibiotic polymyxin B,” the researchers wrote.
“Interestingly, these molecules have a different composition from what has traditionally been considered antimicrobial,” said Marcelo Torres, a research associate in the de la Fuente lab, and the paper’s first author. “The compounds we have discovered constitute a new class, and their unique properties will help us understand and expand the sequence space of antimicrobials.”
Furthermore, “identifying prevotellin-2, which has activities on par with one of our antibiotics of last resort, polymyxin B, was very surprising to me,” Bhatt said. “This suggests that mining the human microbiome for new and exciting classes of antimicrobial peptides is a promising path forward for researchers and doctors, and most especially for patients.”
