Effects of the Natural Peptide Crotamine from a South American Rattlesnake on Candida auris, an Emergent Multidrug Antifungal Resistant Human Pathogen

Abstract

Invasive Candida infections are an important growing medical concern and treatment options are limited to a few antifungal drug classes, with limited efficacies depending on the infecting organism. In this scenario, invasive infections caused by multiresistant Candida auris are emerging in several places around the world as important healthcare-associated infections. As antimicrobial peptides (AMPs) exert their activities primarily through mechanisms involving membrane disruption, they have a lower chance of inducing drug resistance than general chemical antimicrobials. Interestingly, we previously described the potent candicidal effect of a rattlesnake AMP, crotamine, against standard and treatment-resistant clinical isolates, with no hemolytic activity. We evaluated the antifungal susceptibility of several Candida spp. strains cultured from different patients by using the Clinical and Laboratory Standards Institute (CLSI) microdilution assay, and the antifungal activity of native crotamine was evaluated by a microbial growth inhibition microdilution assay. Although all Candida isolates evaluated here showed resistance to amphotericin B and fluconazole, crotamine (40–80 µM) exhibited in vitro activity against most isolates tested. We suggest that this native polypeptide from the South American rattlesnake Crotalus durissus terrificus has potential as a structural model for the generation of a new class of antimicrobial compounds with the power to fight against multiresistant Candida spp.

Antifungal Resistance in Candida auris: Molecular Determinants

“…The high rate of antifungal resistance of C. auris, and its great ability to form biofilms, creates the need to look for alternative treatments for the infections caused by this yeast. Among the alternatives that have been explored are natural peptides, phenolic compounds, nitric oxide in nanoparticles, as well as the reuse of drugs such as miltefosine and iodoquinol [11][12][13][14][15][16][17]99]. One of the natural peptides with antimicrobial activity is crotamine, a toxin obtained from the rattlesnake's venom [11].…”

“…The increase in the prevalence of multidrug-resistant C. auris to different groups of antifungals is a cause for alarm, especially considering that there are few treatment options nowadays. The latter has prompted the search for other therapeutic alternatives such as natural peptides, phenolic compounds, nitric oxide nanoparticles, as well as miltefosine and iodoquinol [11][12][13][14][15][16][17]. The conducted researches are promising, as they show that several of these alternatives can be used alone or in combination with other traditional antifungals, which produces a synergistic effect that potentiates fungal destruction.…”

Evaluation of Antifungal Activity of Naja pallida and Naja mossambica Venoms against Three Candida Species

“…It is widely accepted that venom peptides from the group of antimicrobial peptides (AMPs) have antibacterial properties [12]. However, it is suggested that AMPs may also exert some antifungal effects such as Pep5Bj peptide from Bothrops jararaca venom (Viperidae family) [26], crotamine from Crotalus durissus terrificus venom (Viperidae family) [27,28] and cathelicidin from the banded krait Bungarus fasciatus venom (Elapidae family) [29]. However, we were unable to identify AMPs in both NPV and NMV (in this study).…”

Potential of Gallium as an Antifungal Agent

“…Susceptible Candida strains are reference lineages or isolates from patients from São Paulo Hospital (Brazil) and belonging to the collection of the Special Mycology Laboratory, São Paulo Federal University. Multidrug-resistant Candida isolates were previously characterized by our group as resistant to at least two classes of antifungal drugs (Bizerra et al, 2014;Dal Mas et al, 2019). All strains were maintained in glycerol 10% at −80 • C until they were used.…”