Introduction

In response to the alarming rise of drug-resistant bacteria, which has far outpaced the development of conventional antibiotics, our latest research published in Cell has identified a promising new avenue for antibiotic discovery within the human microbiome. As global health faces a severe threat from antibiotic resistance, our team in collaboration with Ami S. Bhatt’s Lab has turned to the microbial communities that inhabit the human body as a potential source of novel treatments.

Microbiome as source of new antibiotics

Microbes are in a continual battle for scarce resources, frequently generating antibiotic compounds as a strategy for chemical defense. We postulated that these interactions among microbes, especially within the human microbiome, might uncover a rich reservoir of novel antibiotics.

Our research focused on peptides—short chains of amino acids known for their potential as innovative antibiotics. Through a comprehensive computational analysis of 444,054 predicted small protein families extracted from 1,773 human metagenomes, we identified 323 promising candidates encoded by small open reading frames (smORFs).

To test these findings, we synthesized 78 peptides and assessed their antimicrobial activity in vitro. Remarkably, 70.5% of these peptides exhibited strong antimicrobial effects. Given their distinct characteristics, which set them apart from previously known antimicrobial peptides, we classified them as smORF-encoded peptides (SEPs), a new type of antibiotic.

This discovery reveals the human microbiome as a previously untapped reservoir of peptide antibiotics. These SEPs showed a multifaceted approach to fighting bacteria: they targeted bacterial membranes, worked synergistically, and even modulated gut commensal populations. This suggests their potential not only in combating dangerous pathogens but also in reshaping microbiome communities for better health.

Among the most promising candidates, prevotellin-2, derived from Prevotella copri, demonstrated effectiveness comparable to the commonly used antibiotic polymyxin B in animal models.

Conclusion

These findings underscore the immense potential of the human microbiome as a source of translatable antimicrobials, with hundreds of SEPs ready for further exploration.

For more information on this study, please refer to the full paper published in Cell: https://www.cell.com/cell/fulltext/S0092-8674(24)00802-X

For more information, please contact:
Machine Biology Group
University of Pennsylvania

Authors:
Marcelo D.T. Torres, Erin F. Brooks, Angela Cesaro, Hila Sberro, Matthew O. Gill, Cosmos Nicolaou, Ami S. Bhatt and Cesar de la Fuente-Nunez.

Published:
August 19, 2024

About Machine Biology Group:
The mission statement of the Machine Biology Group at the University of Pennsylvania is to use the power of machines to accelerate discoveries in biology and medicine.