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

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.

Difficult but Not Impossible: in Search of an Anti-Candida Vaccine

“…In a study involving several Candida species, C. glabrata had the most sensitive MIC and MHC ranges for cobalt treatment. The study concluded that this was due to its inability to form hyphae [14].…”

Reactivity trends of cobalt(III) complexes towards various amino acids based on the properties of the amino acid alkyl chains

“…Furthermore, amino acids act as biocompatible ligands to enhance the therapeutic and medicinal applications of metal complexes. Cobalt(III) amino acid complexes find various applications, such as antifungal (Turecka et al, 2018), antimicrobial (Lv et al, 2006), antibacterial (Stnil et al, 2011) and anticancer agents (Munteanu & Suntharalingam, 2015). Despite many potential applications, conglomerate crystallization catalysed by cobalt(III) was reported more than a decade ago and has since suffered a hiatus.…”

Synthesis, antimicrobial activity, and determination of the lipophilicity of ((cyclohex-3-enylmethylene)hydrazinyl)thiazole derivatives

“…Invasive candidiasis are considered the life-threatening infections associated with high morbidity and mortality (Pappas et al 2016;Hacioglu et al 2018). The mortality rate of bloodstream infections caused by these yeasts was reported to be as high as 40-60% among immunosuppressed and hospitalized patients (Sun et al 2015;Li et al 2018;Turecka et al 2018).…”

“…The incidence of fungal infection is increasing, especially in populations of immunosuppressed individuals (persons with HIV/AIDS or primary immune deficiency) and due to the continuous development of modern medicines, such as organ transplantation, hemodialysis, parenteral nutrition, extensive applicability of catheters or medical implants, cancer chemotherapy, and the widespread use of broad-spectrum antibiotics, glucocorticoids, and immunosuppressants (Turecka et al 2018;Roemer and Krysan 2014;Gomes da Silva Dantas et al 2018). In addition to the predisposing factors of the host, the pathogenicity of Candida species is affected by their virulence factors, such as the polymorphism (growth in two forms, unicellular and filamentous), production of extracellular enzymes (proteases, phospholipases, and hemolysins), as well as the expression of adhesins, which is related to the biofilm formation (on host tissues or on medical device surfaces) (Hacioglu et al 2018;Sun et al 2015;Li et al 2018;Gomes da Silva Dantas et al 2018).…”

“…At present, the available antifungal drugs are limited to three major classes: polyenes (amphotericin B or nystatin), which bind fungal cell membrane ergosterol leading to cell lysis; azoles (fluconazole or posaconazole) that inhibit ergosterol biosynthesis; and echinocandins (caspofungin or micafungin) inhibiting fungal (1,3)-β-D-glucan cell wall synthesis (Ishida et al 2011;Pappas et al 2016;Li et al 2018;Turecka et al 2018;Roemer and Krysan 2014;Ahmad et al 2017). Some characteristics of these drugs restrict their use in prophylaxis and clinical practice, such as fungistatic activity (azoles), which extends the required time of treatment, high toxicity (polyenes) and nonspecific interaction with other drugs, which increases their side effects (Gomes da Silva Dantas et al 2018;Ahmad et al 2017).…”