Harnessing the Power of Gut Bacteria to Combat Drug Resistance

There are approximately 100 trillion microbes in the human gut on average, and many of them are always vying for scarce resources.

It’s such a harsh environment. You have all these bacteria coexisting, but also fighting each other. Such an environment may foster innovation.”

César de la Fuente, Presidential Assistant Professor, Bioengineering and Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania

de la Fuente's lab sees potential for novel antibiotics in that fight, which could eventually add to humanity's defense arsenal against bacteria that are resistant to drugs. In the end, why not turn the bacteria in the stomachs against each other if they must create new tools to combat one another to survive?

The labs of de la Fuente and Ami S. Bhatt, a Stanford Professor of Genetics and Medicine (hematology), analyzed the gut microbiomes of nearly 2,000 individuals and found dozens of putative novel antibiotics in a recent paper published in Cell.

We think of biology as an information source. Everything is just code. And if we can come up with algorithms that can sort through that code, we can dramatically accelerate antibiotic discovery.”

César de la Fuente, Presidential Assistant Professor, Bioengineering and Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania

de la Fuente's lab has garnered media attention in recent years for discovering antibiotic candidates in a variety of places, including the genetic makeup of extinct animals like woolly mammoths and Neanderthals, as well as vast populations of bacteria whose genetic makeup the lab examined using artificial intelligence.

de la Fuente said, “One of our primary goals is to mine the world’s biological information as a source of antibiotics and other useful molecules. 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.”

Bacteria evolve rapidly, leading de la Fuente and his colleagues to speculate that a competitive environment such as the human gut could harbor many unidentified antimicrobial compounds.

de la Fuente pointed out that, “When there is a lack of resources, biology really comes up with innovative solutions.”

Peptides, which are short chains of amino acids, were the group's main focus because they have previously shown promise as novel antibiotics.

“We computationally mined over 400,000 proteins,” concluded de la Fuente referring to the process whereby AI reads the letters of genetic code and the ability to predict which genetic sequences might have antimicrobial properties after being trained on a set of known antibiotics.

Interestingly, these molecules have a different composition from what has traditionally been considered antimicrobial. The compounds we have discovered constitute a new class, and their unique properties will help us understand and expand the sequence space of antimicrobials.”

Marcelo D.T. Torres, Research Associate and Study First Author, University of Pennsylvania

After identifying several hundred antibiotic candidates, the researchers chose 78 to be tested against real bacteria to validate those predictions experimentally. Following the synthesis of these peptides, the scientists exposed bacterial cultures to each one and then watched to see which peptides effectively stopped the growth of the bacteria for 20 hours. Later on, the team used animal models to test the antibiotic candidates.

The lead candidate, prevotellin-2, showed anti-infective capabilities on par with polymyxin B, an FDA-approved antibiotic used today to treat multidrug-resistant infections. This suggests that the human gut microbiome may contain antibiotics that will one day find clinical application. More than half of the peptides tested worked, inhibiting the growth of either friendly or pathogenic bacteria.

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