Silver nanoparticles induced alterations in multiple cellular targets, which are critical for drug susceptibilities and pathogenicity in fungal pathogen (<em>Candida albicans</em>)

Abstract

PurposeA significant increase in the incidence of fungal infections and drug resistance has been observed in the past decades due to limited availability of broad-spectrum antifungal drugs. Nanomedicines have shown significant antimicrobial potential against various drug-resistant microbes. Silver nanoparticles (AgNps) are known for their antimicrobial properties and lower host toxicity; however, for clinical applications, evaluation of their impact at cellular and molecular levels is essential. The present study aims to understand the cellular and molecular mechanisms of AgNp-induced toxicity in a common fungal pathogen, Candida albicans.MethodsAgNps were synthesized by chemical reduction method and characterized using UV–visible spectroscopy, X-ray powder diffraction, transmission electron microscopy, scanning electron microscopy–energy dispersive X-ray spectroscopy, energy dispersive X-ray fluorescence, and zeta potential. The anti-Candida activity of AgNps was assessed by broth microdilution and spot assays. Effects of AgNps on cellular and molecular targets were assessed by monitoring the intracellular reactive oxygen species (ROS) production in the absence and presence of natural antioxidant, changes in surface morphology, cellular ultrastructure, membrane microenvironment, membrane fluidity, membrane ergosterol, and fatty acids.ResultsSpherical AgNps (10–30 nm) showed minimum inhibitory concentration (minimum concentration required to inhibit the growth of 90% of organisms) at 40 μg/mL. Our results demonstrated that AgNps induced dose-dependent intracellular ROS which exerted antifungal effects; however, even scavenging ROS by antioxidant could not offer protection from AgNp mediated killing. Treatment with AgNps altered surface morphology, cellular ultrastructure, membrane microenvironment, membrane fluidity, ergosterol content, and fatty acid composition, especially oleic acid.ConclusionTo summarize, AgNps affected multiple cellular targets crucial for drug resistance and pathogenicity in the fungal cells. The study revealed new cellular targets of AgNps which include fatty acids like oleic acid, vital for hyphal morphogenesis (a pathogenic trait of Candida). Yeast to hypha transition being pivotal for virulence and biofilm formation, targeting virulence might emerge as a new paradigm for developing nano silver-based therapy for clinical applications in fungal therapeutics.

Silver nanoantibiotics display strong antifungal activity against the emergent multidrug-resistant yeastCandida aurisunder both planktonic and biofilm growing conditions

“…In response to these stresses, specific but relatively small changes at the structural or molecular level may increase their probability to resist the action of antifungals, as previously described for C. auris [26,27]. In contrasts, AgNPs cause several simultaneous types of structural and metabolic damage in the Candida cells, such as membrane depolarization [28], cell wall/membrane disruption [29], increase in ROS production [30], inhibit enzymatic function [31], cell arrest [28], among many others. This massive disruption of cellular structure and function reduces their ability to withstand the AgNPs effects.…”

Multifunctional Copper-Containing Mesoporous Glass Nanoparticles as Antibacterial and Proangiogenic Agents for Chronic Wounds

“…Whilst there is some evidence that bacteria can develop resistance mechanisms to certain forms of copper and silver (Percival et al, 2005;Santo et al, 2011;Finley et al, 2015;Hobman and Crossman, 2015;Williams et al, 2016), they are still promising as antimicrobials due to their broad ranges of biocidal activity against multiple microorganisms, including both Gram positive and Gram negative bacteria. Evidence also exists that metal ions such as silver and copper are either directly antifungal or enhance the actions of antifungal agents (Gomes da Silva Dantas et al, 2018;Radhakrishnan et al, 2018).…”

Silver Nanoparticles Offer a Synergistic Effect with Fluconazole Against Fluconazole-Resistant Candida Albicans by Abrogating Drug Efflux Bumps and Increasing Endogenous ROS

“…In wild-type C. albicans strain SC5314, AgNPs exerted antifungal activity by altering membrane microenvironment, predominantly ergosterol content and fatty acid composition [31]. AgNPs could also induce intracellular ROS production [31].…”