Fungicidal potency and mechanisms of {theta}-defensins against multi-drug resistant Candida species [PublishAheadOfPrint]

Systemic candidiasis is a growing health care concern becoming even more challenging due to the growing frequency of infections caused by multidrug resistant (MDR) Candida spp. Thus there is an urgent need for new therapeutic approaches to candidiasis, including strategies bioinspired by insights into natural host defense against fungal pathogens. The antifungal properties of -defensins, macrocyclic peptides expressed in tissues of Old World monkeys, were investigated against a panel of drug sensitive and drug resistant clinical isolates of C. albicans and non-albicans Candida spp. Rhesus -defensin 1 (RTD-1), the prototype -defensin, was rapidly and potently fungicidal against drug sensitive and MDR C. albicans strains. Fungal killing occurred by cell permeabilization that was temporally correlated with ATP release and intracellular accumulation of reactive oxygen species (ROS). Killing by RTD-1 was compared with that of histatin 5 (Hst 5), an extensively characterized anticandidal peptide expressed in human saliva. RTD-1 killed C. albicans much more rapidly and at >200-fold lower concentration than Hst 5. Unlike Hst 5, the anticandidal activity of RTD-1 was independent of mitochondrial ATP production. Moreover, RTD-1 was completely resistant to Candida proteases for 2 h under conditions that rapidly and completely degraded Hst 5. Minimal inhibitory and fungicidal concentrations (MIC/MFC) of 14 natural -defensins isoforms against drug resistant C. albicans isolates identified peptides that are more active than amphotericin B and/or caspofungin against fluconazole resistant organisms, including MDR C. auris. These results point to the potential of macrocyclic -defensins as structural templates for design of antifungal therapeutics.

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