Antifungal Activity and Mechanism of Action of the Co(III) Coordination Complexes With Diamine Chelate Ligands Against Reference and Clinical Strains of Candida spp.

Katarzyna Turecka,Agnieszka Chylewska,Anna Kawiak,Krzysztof F Waleron

doi:10.3389/fmicb.2018.01594

Katarzyna Turecka, Agnieszka Chylewska + Show 2 more

Open Access

https://doi.org/10.3389/fmicb.2018.01594

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Abstract

Although many antifungal agents are available in clinical treatment, increasing resistance of fungi, especially Candida species, to the available drugs requires the development of new safe and non-toxic compounds with novel modes of action as effective treatment against resistant microorganisms. Cobalt complexes are very interesting and attractive as potential candidates with antimicrobial activity. Their therapeutic uses as antiviral, antibacterial antifungal, antiparasitic, antitumour, transferrin transporters, and anti-inflammatory agents are being intensively investigated. In this study we examined the antifungal activity of Co(III) complexes with diamine chelate ligands against a broad spectrum of Candida species. Minimum inhibitory concentration was determined by the microbroth dilution method and with serial passaging assay; the synergistic antimicrobial activity of the tested complexes combined with two antifungal drugs (ketoconazole and amphotericin B) was made by checkerboard assay. The effects of Co(III) complexes on yeast cell morphology were studied by optical and transmission electron microscopy. The mode of action of Co(III) complexes on the yeast cell wall (sorbitol assay) and cell membrane (ergosterol assay) were investigated. The cytotoxic effects of the tested compounds on red blood cells and the human keratinocyte (HaCaT) cell line were also evaluated. The analyzed compounds revealed significant antifungal activity for selected strains of Candida species; [CoCl2(dap)2]Cl (1) and [CoCl2(en)2]Cl (2) were more effective than ketoconazole. Its probable mechanism of action did not involve the cell wall or ergosterol binding. However, the checkerboard assay showed, that the antifungal activity of ketoconazole increased in combination with the tested complexes of Co(III). Our results suggest that both diamine complexes with Co(III) analogs caused damage to mitochondrial membrane or the membrane of the endoplasmic reticulum. The effect was observed by transmission electron microscope. Co(III) complexes with diamine chelate ligands are non-toxic at concentrations active against Candida species. This study provides new data on potential antifungal drugs, especially against Candida species.

Highlights

Candida spp., in particular Candida albicans, is one of the most important opportunistic fungal pathogens, which can harmlessly colonize the gastrointestinal tract, mouth, skin and urogenital system (Wu et al, 2003; Jackson et al, 2007; Achkar and Fries, 2010; Rosenbach et al, 2010; Naglik et al, 2011)
Risk factors that are conducive to the development of systemic infections caused by Candida include: long-term stay in intensive care units, surgery, broad-spectrum antibiotic intake, and immunosuppressants (Kontoyiannis et al, 2003; Pfaller and Diekema, 2004; Zaoutis et al, 2005; Sydnor and Perl, 2011)
Other species of Candida increasingly isolated from patients are Candida glabrata, Candida tropicalis, Candida parapsilosis, and Candida krusei (MacCallum, 2012)

Summary

Introduction

Candida spp., in particular Candida albicans, is one of the most important opportunistic fungal pathogens, which can harmlessly colonize the gastrointestinal tract, mouth, skin and urogenital system (Wu et al, 2003; Jackson et al, 2007; Achkar and Fries, 2010; Rosenbach et al, 2010; Naglik et al, 2011) It can cause infections, especially among people with weakened immune systems, attacking the skin, mucous membranes, getting into the blood, and attacking internal organs. Despite the availability of treatment using antifungal agents, the high morbidity and mortality rates associated with candidiasis (Pfaller and Diekema, 2007) and the growing resistance of yeast to antifungals requires the development of novel compounds with novel mechanisms of action. Major targets for potential antifungal agents are: (1) ergosterol (inhibiting its biosynthesis or binding to it), an essential lipid of the yeast cell membrane (not present in mammalian cells); and (2) chitin and β-glucan (inhibition of its synthesis), key structural components of the fungal cell wall (Hof, 2006; Sundriyal et al, 2006; Pierce et al, 2013; Ngo et al, 2016)

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