The human body houses trillions of bacteria that make up the microbiome. When a microbial imbalance occurs, e.g., in the intestines, pathogenic bacteria can fill the void left by good bacteria, resulting in various diseases. Persulfides (RSSH) are reducing species that can modulate and improve the microbiome redox environment.
John B. Matson, Irving C. Allen, and colleagues, Virginia Tech, Blacksburg, USA, have designed a drug precursor that decomposes in the gut to release a persulfide in response to the bacterial enzyme nitroreductase. The persulfide donor, called nitroreductase disulfide prodrug-N-acetylcysteine (NDP-NAC, pictured), releases its persulfide payload over several hours. NDP-NAC was synthesized in four steps starting from p‐nitrotoluene, which was brominated using N‐bromosuccinimide (NBS). A reaction with thiourea, followed by aminolysis using hexylamine, then gave p‐nitrobenzyl thiol. Finally, the thiol was added to an activated disulfide of N-acetylcysteine (NACpyDS), and a disulfide exchange reaction gave the desired prodrug in an overall yield of 35 %.
The prodrug increased concentrations of the beneficial medium-chain fatty acid heptanoic acid in the gut, which may induce gastroprotective effects. The team investigated how levels of gut bacteria in mice changed upon NDP-NAC administration and found that the prodrug increased levels of the beneficial bacterium Turicibacter sanguinis, while decreasing levels of Synergistales bacteria, which are associated with gastrointestinal infections. Overall, NDP-NAC improved the makeup of the gut microbiome in mice by increasing levels of beneficial bacteria while limiting pathogenic bacteria. This work suggests that persulfides may play an important natural role in the regulation of the microbiome and that the controlled delivery of persulfides may be useful for treating microbiome-related diseases.
- Targeted Delivery of Persulfides to the Gut: Effects on the Microbiome,
Kearsley M. Dillon, Holly A. Morrison, Chadwick R. Powell, Ryan J. Carrazzone, Veronica M. Ringelâ€Scaia, Ethan W. Winckler, R. McAlister Council-Troche, Irving C. Allen, John B. Matson,
Angew. Chem. Int. Ed. 2021.