The Repurposed Drug Disulfiram Inhibits Urease and Aldehyde Dehydrogenase and Prevents In Vitro Growth of the Oomycete Pythium insidiosum

is an oomycete microorganism that causes a life-threatening infectious disease, called pythiosis, in humans and animals. The disease has been increasingly reported worldwide. Conventional antifungal drugs are ineffective against Treatment of pythiosis requires the extensive removal of infected tissu...

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Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2019-08, Vol.63 (8)
Main Authors: Krajaejun, Theerapong, Lohnoo, Tassanee, Yingyong, Wanta, Rujirawat, Thidarat, Kumsang, Yothin, Jongkhajornpong, Passara, Theerawatanasirikul, Sirin, Kittichotirat, Weerayuth, Reamtong, Onrapak, Yolanda, Hanna
Format: Article
Language:English
Subjects:
Acetaldehyde Dehydrogenase Inhibitors
Acetaldehyde Dehydrogenase Inhibitors - pharmacology
Aldehyde Dehydrogenase
Aldehyde Dehydrogenase - antagonists & inhibitors
Animals
Antifungal Agents - pharmacology
Disulfiram
Disulfiram - pharmacology
Humans
Molecular Docking Simulation - methods
Oomycetes
Oomycetes - drug effects
Pythiosis - drug therapy
Pythiosis - microbiology
Pythium
Pythium - drug effects
Susceptibility
Urease
Urease - antagonists & inhibitors
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Summary:is an oomycete microorganism that causes a life-threatening infectious disease, called pythiosis, in humans and animals. The disease has been increasingly reported worldwide. Conventional antifungal drugs are ineffective against Treatment of pythiosis requires the extensive removal of infected tissue (i.e., eye and leg), but inadequate surgery and recurrent infection often occur. A more effective treatment is needed for pythiosis patients. Drug repurposing is a promising strategy for the identification of a U.S. Food and Drug Administration-approved drug for the control of Disulfiram has been approved to treat alcoholism, but it exhibits antimicrobial activity against various pathogens. In this study, we explored whether disulfiram possesses an anti- activity. A total of 27  strains, isolated from various hosts and geographic areas, were susceptible to disulfiram in a dose-dependent manner. The MIC range of disulfiram against (8 to 32 mg/liter) was in line with that of other pathogens. Proteogenomic analysis indicated that several potential targets of disulfiram (i.e., aldehyde dehydrogenase and urease) were present in By homology modeling and molecular docking, disulfiram can bind the putative aldehyde dehydrogenase and urease of at low energies (i.e., -6.1 and -4.0 Kcal/mol, respectively). Disulfiram diminished the biochemical activities of these enzymes. In conclusion, disulfiram can inhibit the growth of many pathogenic microorganisms, including The drug can bind and inactivate multiple proteins of , which may contribute to its broad antimicrobial property. Drug repurposing of disulfiram could be a new treatment option for pythiosis.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.00609-19