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Human gut metagenomic mining reveals an untapped source of peptide antibiotics

Drug-resistant bacteria are outpacing traditional antibiotic discovery efforts. Here, we computationally mined 444,054 families of putative small proteins from 1,773 human gut metagenomes, identifying 323 peptide antibiotics encoded in small open reading frames (smORFs). To test our computational pr...

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Autores principales: Torres, Marcelo D. T., Brooks, Erin, Cesaro, Angela, Sberro, Hila, Nicolaou, Cosmos, Bhatt, Ami S., de la Fuente-Nunez, Cesar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10491270/
https://www.ncbi.nlm.nih.gov/pubmed/37693399
http://dx.doi.org/10.1101/2023.08.31.555711
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author Torres, Marcelo D. T.
Brooks, Erin
Cesaro, Angela
Sberro, Hila
Nicolaou, Cosmos
Bhatt, Ami S.
de la Fuente-Nunez, Cesar
author_facet Torres, Marcelo D. T.
Brooks, Erin
Cesaro, Angela
Sberro, Hila
Nicolaou, Cosmos
Bhatt, Ami S.
de la Fuente-Nunez, Cesar
author_sort Torres, Marcelo D. T.
collection PubMed
description Drug-resistant bacteria are outpacing traditional antibiotic discovery efforts. Here, we computationally mined 444,054 families of putative small proteins from 1,773 human gut metagenomes, identifying 323 peptide antibiotics encoded in small open reading frames (smORFs). To test our computational predictions, 78 peptides were synthesized and screened for antimicrobial activity in vitro, with 59% displaying activity against either pathogens or commensals. Since these peptides were unique compared to previously reported antimicrobial peptides, we termed them smORF-encoded peptides (SEPs). SEPs killed bacteria by targeting their membrane, synergized with each other, and modulated gut commensals, indicating that they may play a role in reconfiguring microbiome communities in addition to counteracting pathogens. The lead candidates were 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. We report the discovery of hundreds of peptide sequences in the human gut.
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spelling pubmed-104912702023-09-09 Human gut metagenomic mining reveals an untapped source of peptide antibiotics Torres, Marcelo D. T. Brooks, Erin Cesaro, Angela Sberro, Hila Nicolaou, Cosmos Bhatt, Ami S. de la Fuente-Nunez, Cesar bioRxiv Article Drug-resistant bacteria are outpacing traditional antibiotic discovery efforts. Here, we computationally mined 444,054 families of putative small proteins from 1,773 human gut metagenomes, identifying 323 peptide antibiotics encoded in small open reading frames (smORFs). To test our computational predictions, 78 peptides were synthesized and screened for antimicrobial activity in vitro, with 59% displaying activity against either pathogens or commensals. Since these peptides were unique compared to previously reported antimicrobial peptides, we termed them smORF-encoded peptides (SEPs). SEPs killed bacteria by targeting their membrane, synergized with each other, and modulated gut commensals, indicating that they may play a role in reconfiguring microbiome communities in addition to counteracting pathogens. The lead candidates were 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. We report the discovery of hundreds of peptide sequences in the human gut. Cold Spring Harbor Laboratory 2023-09-03 /pmc/articles/PMC10491270/ /pubmed/37693399 http://dx.doi.org/10.1101/2023.08.31.555711 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Torres, Marcelo D. T.
Brooks, Erin
Cesaro, Angela
Sberro, Hila
Nicolaou, Cosmos
Bhatt, Ami S.
de la Fuente-Nunez, Cesar
Human gut metagenomic mining reveals an untapped source of peptide antibiotics
title Human gut metagenomic mining reveals an untapped source of peptide antibiotics
title_full Human gut metagenomic mining reveals an untapped source of peptide antibiotics
title_fullStr Human gut metagenomic mining reveals an untapped source of peptide antibiotics
title_full_unstemmed Human gut metagenomic mining reveals an untapped source of peptide antibiotics
title_short Human gut metagenomic mining reveals an untapped source of peptide antibiotics
title_sort human gut metagenomic mining reveals an untapped source of peptide antibiotics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10491270/
https://www.ncbi.nlm.nih.gov/pubmed/37693399
http://dx.doi.org/10.1101/2023.08.31.555711
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