Abstract
Background. Candida auris has spread rapidly around the world as a causative agent of invasive candidiasis in health care facilities and there is an urgent need to find new options for treating this emerging, often multidrug-resistant pathogen. Methods. We screened the Pathogen Box® chemical library for inhibitors of C. auris strain 0390, both under planktonic and biofilm growing conditions. Results. The primary screen identified 12 compounds that inhibited at least 60% of biofilm formation or planktonic growth. After confirmatory dose-response assays, iodoquinol and miltefosine were selected as the two main leading repositionable compounds. Iodoquinol displayed potent in vitro inhibitory activity against planktonic C. auris but showed negligible inhibitory activity against biofilms; whereas miltefosine was able to inhibit the growth of C. auris under both planktonic and biofilm-growing conditions. Subsequent experiments confirmed their activity against nine other strains C. auris clinical isolates, irrespective of their susceptibility profiles against conventional antifungals. We extended our studies further to seven different species of Candida, also with similar findings. Conclusion. Both drugs possess broad spectrum of activity against Candida spp., including multiple strains of the emergent C. auris, and may constitute promising repositionable options for the development of novel therapeutics for the treatment of candidiasis.
Highlights
Candidiasis is the third to fourth most common cause of nosocomial bloodstream infections in hospitalized patients in the United States [1,2,3,4], and invasive candidiasis carries mortality rates close to40% [5]
A total of three compounds in the Pathogen Box® library were capable of inhibiting C. auris biofilm formation by 60% or more at 20 μM, with only two of those representing hits when the screen was conducted at the lower concentration, though one other compound not identified at 20 μM was found at this concentration
The Pathogen Box® is a diverse library of compounds (400 drug-like molecules) originally assembled by Medicines for Malaria Venture (MMV) with the intention to accelerate the identification of drugs with in vitro activity against neglected diseases caused by parasites, including Malaria, Leishmaniasis, and Chagas’s disease; worms, including Schistosoma mansoni and hookworm; and bacteria
Summary
Candidiasis is the third to fourth most common cause of nosocomial bloodstream infections in hospitalized patients in the United States [1,2,3,4], and invasive candidiasis carries mortality rates close to40% [5]. The most recent NACS to emerge as a formidable opportunistic pathogen is Candida auris It was first reported in a human ear infection in 2009 in Japan [7], it has been determined retroactively that it was present in an infection in South Korea in 1996 [8]. Candida auris has spread rapidly around the world as a causative agent of invasive candidiasis in health care facilities and there is an urgent need to find new options for treating this emerging, often multidrug-resistant pathogen. Iodoquinol displayed potent in vitro inhibitory activity against planktonic C. auris but showed negligible inhibitory activity against biofilms; whereas miltefosine was able to inhibit the growth of C. auris under both planktonic and biofilm-growing conditions Subsequent experiments confirmed their activity against nine other strains C. auris clinical isolates, irrespective of their susceptibility profiles against conventional antifungals. Both drugs possess broad spectrum of activity against Candida spp., including multiple strains of the emergent C. auris, and may constitute promising repositionable options for the development of novel therapeutics for the treatment of candidiasis
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