Abstract
Background: Infections caused by Candida spp. have become one of the major causes of morbidity and mortality in immunocompromised patients. Therefore, new effective fungicides are urgently needed, especially due to an escalating resistance crisis. Methods: A set of nanosystems with rod- (AuR), peanut- (AuP), and star-shaped (AuS) metal cores were synthesized. These gold nanoparticles were conjugated with ceragenins CSA-13, CSA-44, and CSA-131, and their activity was evaluated against Candida strains (n = 21) through the assessment of MICs (minimum inhibitory concentrations)/MFCs (minimum fungicidal concentrations). Moreover, in order to determine the potential for resistance development, serial passages of Candida cells with tested nanosystems were performed. The principal mechanism of action of Au NPs was evaluated via ROS (reactive oxygen species) generation assessment, plasma membrane permeabilization, and release of the protein content. Finally, to evaluate the potential toxicity of Au NPs, the measurement of hemoglobin release from red blood cells (RBCs) was carried out. Results: All of the tested nanosystems exerted a potent candidacidal activity, regardless of the species or susceptibility to other antifungal agents. Significantly, no resistance development after 25 passages of Candida cells with AuR@CSA-13, AuR@CSA-44, and AuR@CSA-131 nanosystems was observed. Moreover, the fungicidal mechanism of action of the investigated nanosystems involved the generation of ROS, damage of the fungal cell membrane, and leakage of intracellular contents. Notably, no significant RBCs hemolysis at candidacidal doses of tested nanosystems was detected. Conclusions: The results provide rationale for the development of gold nanoparticles of rod-, peanut-, and star-shaped conjugated with CSA-13, CSA-44, and CSA-131 as effective candidacidal agents.
Highlights
Clinical strains of Candida were collected from hematooncological patients of Holy Cross Cancer Center in Kielce (Kielce, Poland), and reference strains were purchased from the Polish Collection of Microorganisms, Polish
The identification and antifungal sensitivity of Candida strains used in this study was determined using a VITEK® 2 utilizing fungal cards YST and YS08. This system allows for an assessment of the antimycotic susceptibility of fungi to amphotericin B (AMB), caspofungin (CSF), fluconazole (FLU), flucytosine (FC), micafungin (MCF), and voriconazole (VOR)
The microdilution method described in the guidelines of the European Committee on Antimicrobial Susceptibility Testing (EUCAST), version 10.0-valid from 4 February 2020, was used to determine the minimum inhibitory concentrations (MICs) of the tested agents against fungal strains suspended at populations of 2 × 105 CFU/mL
Summary
The incidences of Candida fungal infections have substantially increased. The attributable mortality among all patients with candidaemia has been recorded to be between 10% and 47%; a more accurate estimate is approximately 10–20%, with the risk of death being strictly connected with the increasing age, the species of Candida strain causing the infection, the use of immunosuppressive agents, and the presence of the venous catheter, as well as pre-existing renal dysfunction and other comorbidities [1,2,3,4,5]. It is worth emphasizing that nearly 10 million cases of mucosal candidiasis are reported globally and more than 150 million of people are affected by serious fungal diseases [6]. Candida infections induce more than 3.6 million healthcare visits each year in the USA, resulting in $3 billion of direct medical costs [7]
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