Fungicidal Potency and Mechanisms of θ-Defensins against Multidrug-Resistant Candida Species

Abstract

Systemic candidiasis is a growing health care concern that is becoming even more challenging due to the growing frequency of infections caused by multidrug-resistant (MDR) species. 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 θ-defensins, macrocyclic peptides expressed in tissues of Old World monkeys, were investigated against a panel of drug-sensitive and drug-resistant clinical isolates of and non- species. Rhesus θ-defensin 1 (RTD-1), the prototype θ-defensin, was rapidly and potently fungicidal against drug-sensitive and MDR 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 by histatin 5 (Hst 5), an extensively characterized anticandidal peptide expressed in human saliva. RTD-1 killed much more rapidly and at a >200-fold lower concentration than that of Hst 5. Unlike Hst 5, the anticandidal activity of RTD-1 was independent of mitochondrial ATP production. Moreover, RTD-1 was completely resistant to proteases for 2 h under conditions that rapidly and completely degraded Hst 5. MICs and minimum fungicidal concentrations (MFCs) of 14 natural θ-defensins isoforms against drug-resistant isolates identified peptides that are more active than amphotericin B and/or caspofungin against fluconazole-resistant organisms, including MDR These results point to the potential of macrocyclic θ-defensins as structural templates for the design of antifungal therapeutics.

Soyuretox, an Intrinsically Disordered Polypeptide Derived from Soybean (Glycine Max) Ubiquitous Urease with Potential Use as a Biopesticide

“…Various antimicrobial peptides that are active against Candida species induce ROS production by the targeted yeasts as part of their antifungal effect: ROS production accompanying the fungitoxic effect were described for the Phaseolus vulgaris (L.) defensin PvD1 against C. albicans at 16 µM concentration [31], the wasp-derived antimicrobial peptide protonectin in doses of 128 and 256 µM, against C. glabrata after a 6 h treatment [32] and the polypeptide arenicin-1, derived from a marine polychaeta, at 9 µM dose [33]. The Rhesus theta-defensin 1 was proven effective against both drug-sensitive and drug-resistant clinical isolates of C. albicans and non-albicans Candida spp., in the 1.5–3.0 µM concentration range, with fungal killing occurring by intracellular accumulation ROS and cell permeabilization [34].…”

Epidemiology, clinical characteristics, resistance, and treatment of infections by Candida auris

“…Moreover, this drug is not affected by common mutations in protein targets and is orally bioavailable [ 97 ]. Recently, Basso et al described the antifungal properties of θ-defensins, 18-aminoacid macrocyclic peptides with potential applications for therapeutic treatment of systemic MDR infections, representing a template for the future development of new antifungals generation [ 98 ]. APX001 is a broad-spectrum antifungal agent for the treatment of invasive fungal infections, including species resistant to other antifungal drug classes, inhibiting an enzyme ( Gwt1 ) part of the glycosylphosphatidylinositol (GPI) biosynthesis pathway [ 99 ].…”

Bio- and Nanotechnology as the Key for Clinical Application of Salivary Peptide Histatin: A Necessary Advance

“…A recent study conducted by Basso et al showed that the ATP efflux caused by histatin-5 is slow and prolonged and leads to a slower cell death compared to the peptide RTD-1 used in this study [99]. Despite that, recently Pathirana et al proved the effectiveness of this peptide in inhibiting seven resistant strains of C. auris, a multidrug resistance microorganism.…”