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Title: The repurposed drug disulfiram inhibits urease and aldehyde dehydrogenase and prevents in vitro growth of the oomycete pythium insidiosum
Authors: Theerapong Krajaejun
Tassanee Lohnoo
Wanta Yingyong
Thidarat Rujirawat
Yothin Kumsang
Passara Jongkhajornpong
Sirin Theerawatanasirikul
Weerayuth Kittichotirat
Onrapak Reamtong
Hanna Yolanda
Universitas Katolik Indonesia Atma Jaya
Kasetsart University
Faculty of Medicine, Ramathibodi Hospital, Mahidol University
Mahidol University
King Mongkut s University of Technology Thonburi
Keywords: Medicine
Issue Date: 1-Jan-2019
Citation: Antimicrobial Agents and Chemotherapy. Vol.63, No.8 (2019)
Abstract: Copyright © 2019 American Society for Microbiology. All Rights Reserved. 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 P. insidiosum. 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 P. insidiosum. 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-P. insidiosum activity. A total of 27 P. insidiosum strains, isolated from various hosts and geographic areas, were susceptible to disulfiram in a dose-dependent manner. The MIC range of disulfiram against P. insidiosum (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 P. insidiosum. By homology modeling and molecular docking, disulfiram can bind the putative aldehyde dehydrogenase and urease of P. insidiosum 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 P. insidiosum. The drug can bind and inactivate multiple proteins of P. insidiosum, which may contribute to its broad antimicrobial property. Drug repurposing of disulfiram could be a new treatment option for pythiosis.
ISSN: 10986596
Appears in Collections:Scopus 2019

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