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Drug Metabolism & Disposition

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Gut microbiome-wide search for bacterial azoreductases reveals potentially uncharacterized azoreductases encoded in the human gut microbiome

Domenick J. Braccia, Glory Minabou Ndjite, Ashley Weiss, Sophia Levy, Stephenie Abeysinghe, Xiaofang Jiang, Mihai Pop and Brantley Hall
Drug Metabolism and Disposition September 18, 2022, DMD-AR-2022-000898; DOI: https://doi.org/10.1124/dmd.122.000898
Domenick J. Braccia
1
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Glory Minabou Ndjite
2University of Maryland, United States
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Ashley Weiss
2University of Maryland, United States
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Sophia Levy
2University of Maryland, United States
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Stephenie Abeysinghe
2University of Maryland, United States
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Xiaofang Jiang
3National Library of Medicine, National Institutes of Health, United States
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Mihai Pop
4Computer Science, University of Maryland, United States
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Brantley Hall
5Cell Biology and Molecular Genetics, University of Maryland, United States
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  • For correspondence: brantley@umd.edu
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Abstract

The human gut is home to trillions of microorganisms that are responsible for the modification of many orally administered drugs, leading to a wide range of therapeutic outcomes. Prodrugs bearing an azo bond are designed to treat inflammatory bowel disease (IBD) and colorectal cancer (CRC) via microbial azo reduction, allowing for topical application of therapeutic moieties to the diseased tissue in the intestines. Despite the inextricable link between microbial azo reduction and the efficacy of azo prodrugs, the prevalence, abundance, and distribution of azoreductases have not been systematically examined across the gut microbiome. Here, we curated and clustered amino acid sequences of experimentally confirmed bacterial azoreductases and conducted a Hidden Markov Model (HMM)-driven homolog search for these enzymes across 4,644 genome sequences present in the representative Unified Human Gastrointestinal Genomes (UHGG) collection. We identified 1,958 putative azo-reducing species, corroborating previous findings that azo reduction appears to be a ubiquitous function of the gut microbiome. However, through a systematic comparison of predicted and confirmed azo-reducing strains, we hypothesize the presence of uncharacterized azoreductases in 25 prominent strains of the human gut microbiome. Finally, we confirmed the azo reduction of Acid Orange 7 by multiple strains of Fusobacterium nucleatum, Bacteroides fragilis, and Clostridium clostridioforme. Together, these results suggest the presence and activity of many uncharacterized azoreductases in the human gut microbiome and motivate future studies aimed at characterizing azoreductase genes in prominent members of the human gut microbiome.

Significance Statement In this work, we systematically examined the prevalence, abundance, and distribution of azoreductases across the healthy and IBD human gut microbiome revealing potentially uncharacterized azoreductase genes. We also confirmed the reduction of Acid Orange 7 by strains of Fusobacterium nucleatum, Bacteroides fragilis, and Clostridium clostridioforme.

  • bioinformatics
  • drug metabolism
  • microbiome
  • prodrugs
  • targeted drug delivery
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 51 (10)
Drug Metabolism and Disposition
Vol. 51, Issue 10
1 Oct 2023
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Prediction of uncharacterized azo reduction by the gut microbiome

Domenick J. Braccia, Glory Minabou Ndjite, Ashley Weiss, Sophia Levy, Stephenie Abeysinghe, Xiaofang Jiang, Mihai Pop and Brantley Hall
Drug Metabolism and Disposition September 18, 2022, DMD-AR-2022-000898; DOI: https://doi.org/10.1124/dmd.122.000898

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Prediction of uncharacterized azo reduction by the gut microbiome

Domenick J. Braccia, Glory Minabou Ndjite, Ashley Weiss, Sophia Levy, Stephenie Abeysinghe, Xiaofang Jiang, Mihai Pop and Brantley Hall
Drug Metabolism and Disposition September 18, 2022, DMD-AR-2022-000898; DOI: https://doi.org/10.1124/dmd.122.000898
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