Human Microbiome Mined for Antimicrobial Peptides

In a study published recently in Cell, researchers from University of Pennsylvania and Stanford surveyed the gut microbiomes of nearly 2,000 people, discovering dozens of potential new antibiotics.

 In recent years, senior author Cesar de la Fuente has made headlines for finding antibiotic candidates everywhere from the genetic information of extinct creatures like the wooly mammoth to masses of bacteria whose genetic material the lab analyzed using artificial intelligence.   “One of our primary goals is to mine the world's biological information as a source of antibiotics and other useful molecules,” says de la Fuente. “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.”

Given that bacteria evolve quickly, de la Fuente and his coauthors hypothesized that an environment that encourages competition—like the human gut—might be home to numerous undiscovered antimicrobial compounds. “When there is a lack of resources,” de la Fuente points out, “that’s when biology really comes up with innovative solutions.”

The group focused on peptides that had previously shown promise as novel antibiotics. “We computationally mined over 400,000 proteins. “Interestingly, these molecules have a different composition from what has traditionally been considered antimicrobial,” says Marcelo D.T. Torres, 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.”

Of course, those predictions must then be experimentally validated; after finding a few hundred antibiotic candidates, the researchers selected 78 to test against actual bacteria. After synthesizing these peptides, the researchers exposed bacterial cultures to each peptide and waited 20 hours to see which peptides successfully inhibited bacterial growth. In addition, the team later tested the antibiotic candidates in animal models.

Over half of the peptides tested worked—that is, they inhibited bacterial growth of either friendly or pathogenic bacteria—and the lead candidate, prevotellin-2, demonstrated anti-infective capabilities on par with polymyxin B, an FDA-approved antibiotic used today to treat multidrug-resistant infections, suggesting that the human gut microbiome may contain antibiotics that will someday find clinical application.

“Identifying prevotellin-2, which has activities on par with one of our antibiotics of last resort, polymyxin B, was very surprising to me,” says co-author Ami S. Bhatt. “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.”