Targeted Delivery of Persulfides to the Gut: Effects on the Microbiome

Persulfides (R−SSH) have been hypothesized as potent redox modulators and signaling compounds. Reported herein is the synthesis, characterization, and in vivo evaluation of a persulfide donor that releases N‐acetyl cysteine persulfide (NAC‐SSH) in response to the prokaryote‐specific enzyme nitroredu...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2021-03, Vol.60 (11), p.6061-6067
Main Authors: Dillon, Kearsley M., Morrison, Holly A., Powell, Chadwick R., Carrazzone, Ryan J., Ringel‐Scaia, Veronica M., Winckler, Ethan W., Council‐Troche, R. McAlister, Allen, Irving C., Matson, John B.
Format: Article
Language:English
Subjects:
Acetylcysteine
Animals
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Bacteria
Digestive system
Digestive tract
drug delivery
Drug Design
E coli
Escherichia coli - drug effects
Fatty acids
Gastrointestinal Microbiome - drug effects
inflammation
Kinetics
Listeria monocytogenes - drug effects
Mice
Microbial Sensitivity Tests
microbiome
Microbiomes
Modulators
Molecular Structure
Nitroreductase
Opportunist infection
Oxidative stress
Prodrugs - chemical synthesis
Prodrugs - chemistry
Prodrugs - pharmacology
Sodium sulfide
Staphylococcus aureus - drug effects
stimuli responsiveness
Sulfides - chemical synthesis
Sulfides - chemistry
Sulfides - pharmacology
Sulfur
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Summary:Persulfides (R−SSH) have been hypothesized as potent redox modulators and signaling compounds. Reported herein is the synthesis, characterization, and in vivo evaluation of a persulfide donor that releases N‐acetyl cysteine persulfide (NAC‐SSH) in response to the prokaryote‐specific enzyme nitroreductase. The donor, termed NDP‐NAC, decomposed in response to E. coli nitroreductase, resulting in release of NAC‐SSH. NDP‐NAC elicited gastroprotective effects in mice that were not observed in animals treated with control compounds incapable of persulfide release or in animals treated with Na2S. NDP‐NAC induced these effects by the upregulation of beneficial small‐ and medium‐chain fatty acids and through increasing growth of Turicibacter sanguinis, a beneficial gut bacterium. It also decreased the populations of Synergistales bacteria, opportunistic pathogens implicated in gastrointestinal infections. This study reveals the possibility of maintaining gut health or treating microbiome‐related diseases by the targeted delivery of reactive sulfur species. The persulfide donor NDP‐NAC (see structure) was synthesized and found to decompose in response to E. coli nitroreductase with the release of N‐acetyl cysteine persulfide (NAC‐SSH). NDP‐NAC elicited gastroprotective effects in mice by the upregulation of beneficial small‐ and medium‐chain fatty acids, by increasing growth of Turicibacter sanguinis, a beneficial gut bacterium, and by decreasing populations of pathogenic Synergistales bacteria.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202014052