WMR Peptide as Antifungal and Antibiofilm against Albicans and Non-Albicans Candida Species: Shreds of Evidence on the Mechanism of Action.

Angela Maione,Stefania Galdiero,Alessandra La La Pietra,Emilia Galdiero,Ermenegilda Parrilli,Annarita Falanga,Rosa Bellavita,Luisa Albarano,Elisabetta De De Alteriis,Caterina D’Angelo,Marco Guida

doi:10.3390/ijms23042151

Abstract

Candida species are the most common fungal pathogens infecting humans and can cause severe illnesses in immunocompromised individuals. The increased resistance of Candida to traditional antifungal drugs represents a great challenge in clinical settings. Therefore, novel approaches to overcome antifungal resistance are desired. Here, we investigated the use of an antimicrobial peptide WMR against Candida albicans and non-albicans Candida species in vitro and in vivo. Results showed a WMR antifungal activity on all Candida planktonic cells at concentrations between 25 μM to >50 μM and exhibited activity at sub-MIC concentrations to inhibit biofilm formation and eradicate mature biofilm. Furthermore, in vitro antifungal effects of WMR were confirmed in vivo as demonstrated by a prolonged survival rate of larvae infected by Candida species when the peptide was administered before or after infection. Additional experiments to unravel the antifungal mechanism were performed on C. albicans and C. parapsilosis. The time-killing curves showed their antifungal activity, which was further confirmed by the induced intracellular and mitochondrial reactive oxygen species accumulation; WMR significantly suppressed drug efflux, down-regulating the drug transporter encoding genes CDR1. Moreover, the ability of WMR to penetrate within the cells was demonstrated by confocal laser scanning microscopy. These findings provide novel insights for the antifungal mechanism of WMR against Candida albicans and non-albicans, providing fascinating scenarios for the identification of new potential antifungal targets.

Highlights

The five most common Candida species, Candida albicans, Candida glabrata, Candida parapsilosis, Candida auris, and Candida tropicalis, with C. albicans being the most commonly isolated fungal pathogen in clinical settings, are considered responsible for over 90% of reported cases of invasive candidiasis, in which Candida spreads to the blood or other body organs
The epidemics related to yeast infections and resistance issues to available antifungal drugs are rapidly increasing; non-albicans Candida species and rare yeast species are emerging as major opportunistic pathogens
As biofilm formation is critical for the development of fungal resistance, we first showed that WMR exhibited antifungal activity against planktonic cells and biofilm cells of C. albicans and non-albicans Candida species in vitro

Summary

Introduction

The five most common Candida species, Candida albicans, Candida glabrata, Candida parapsilosis, Candida auris, and Candida tropicalis, with C. albicans being the most commonly isolated fungal pathogen in clinical settings, are considered responsible for over 90% of reported cases of invasive candidiasis, in which Candida spreads to the blood or other body organs. The non-albicans Candida (NAC) have been increasingly reported globally as emerging multidrug-resistant species [1,2] due to the wide use of prophylactic antifungal treatments, the utilization of invasive medical devices and their biofilm formation capacity. The compounds currently available in the clinics are polyenes (Amphotericin B), azoles and echinocandins, which induce increasing resistance, in hospital opportunistic infections [7], as in the case of C. auris, known for its high propensity for developing multidrug resistance which favors nosocomial transmission [8]

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