Potentiation of azole antifungals by 2-adamantanamine

  1. Get@NRC: Potentiation of azole antifungals by 2-adamantanamine (Opens in a new window)
DOIResolve DOI: http://doi.org/10.1128/AAC.00294-13
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Journal titleAntimicrobial Agents and Chemotherapy
Pages35853592; # of pages: 8
Subject2 adamantanamine; amantadine derivative; antifungal agent; ergosterol; fluconazole; miconazole; rimantadine; transcriptome; unclassified drug; voriconazole; biofilm; Candida albicans; controlled study; drug efficacy; drug potentiation; drug screening; fungicidal activity; fungus growth; genetic analysis; guinea pig; human cell; human tissue; IC 50; skin candidiasis
AbstractAzoles are among the most successful classes of antifungals. They act by inhibiting 14 lanosterol demethylase in the ergosterol biosynthesis pathway. Oropharyngeal candidiasis (OPC) occurs in about 90% of HIV-infected individuals, and 4 to 5%are refractory to current therapies, including azoles, due to the formation of resistant biofilms produced in the course of OPC. We reasoned that compounds affecting a different target may potentiate azoles to produce increased killing and an antibiofilm therapeutic. 2-Adamantanamine (AC17) was identified in a screen for compounds potentiating the action of miconazole against biofilms of Candida albicans. AC17, a close structural analog to the antiviral amantadine, did not affect the viability of C. albicans but caused the normally fungistatic azoles to become fungicidal. Transcriptome analysis of cells treated with AC17 revealed that the ergosterol and filamentation pathways were affected. Indeed, cells exposed to AC17 had decreased ergosterol contents and were unable to invade agar. In vivo, the combination of AC17 and fluconazole produced a significant reduction in fungal tissue burden in a guinea pig model of cutaneous candidiasis, while each treatment alone did not have a significant effect. The combination of fluconazole and AC17 also showed improved efficacy (P value of 0.018) compared to fluconazole alone when fungal lesions were evaluated. AC17 is a promising lead in the search for more effective antifungal therapeutics.
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AffiliationHuman Health Therapeutics; National Research Council Canada
Peer reviewedYes
NPARC number21270360
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Record identifiere008d068-8f31-416f-b78a-c9f4bc42a576
Record created2014-02-05
Record modified2016-05-09
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