Abstract
Background Cryptococcosis is a fungal disease of bad prognosis due to its pathogenicity and the toxicity of the drugs used for its treatment. The aim of this study was to investigate the medicinal potential of carbazole and β-carboline alkaloids and derivatives against Cryptococcus neoformans and C. gattii. Methods MICs were established in accordance with the recommendations of the Clinical and Laboratory Standards Institute for alkaloids and derivatives against C. neoformans and C. gattii genotypes VNI and VGI, respectively. A single active compound was further evaluated against C. neoformans genotypes VNII, VNIII, and VNIV, C. gattii genotypes VGI, VGIII, and VGIV, Candida albicans ATCC 36232, for cytotoxicity against the MRC-5 lineage of human fibroblasts and for effects on fungal cells (cell wall, ergosterol, and leakage of nucleic acids). Results Screening of 11 compounds revealed 8-nitroharmane as a significant inhibitor (MIC 40 μg/mL) of several C. neoformans and C. gattii genotypes. It was not toxic to fibroblasts (IC50 > 50 µg/mL) nor did it alter fungal cell walls or the concentration of ergosterol in C. albicans or C. neoformans. It increased leakage of substances that absorb at 260 nm. Conclusions The synthetic β-carboline 8-nitroharmane significantly inhibits pathogenic Cryptococcus species and is interesting as a lead compound towards new therapy for Cryptococcus infections.
Highlights
Cryptococcosis, a fungal disease caused by Cryptococcus neoformans and C. gattii, occurs predominantly in immunocompromised individuals
Cryptococcus infections occur through inhalation of blastospores and basidiospores that establish a pulmonary infection. ese infections can disseminate to the meninges and brain, causing meningitis or meningoencephalitis [1]. e global incidence and impact of cryptococcosis is estimated to be 624,700 deaths annually, with a broad confidence interval of 125,000 to 1,124,900 [2]
The World Health Organization (WHO) recommends a two-week course of amphotericin B and flucytosine (5-FC) as the initial intensive induction phase and subsequently followed by a stepdown to fluconazole for the consolidation and monitoring phases of treatment for cryptococcal meningitis [3]. e arsenal of treatment options available presently for management is limited, with no new class of antifungal agent exhibiting cryptococcal activity licensed in almost 30 years [4]
Summary
Cryptococcosis, a fungal disease caused by Cryptococcus neoformans and C. gattii, occurs predominantly in immunocompromised individuals. E aim of this study was to investigate the medicinal potential of carbazole and β-carboline alkaloids and derivatives against Cryptococcus neoformans and C. gattii. MICs were established in accordance with the recommendations of the Clinical and Laboratory Standards Institute for alkaloids and derivatives against C. neoformans and C. gattii genotypes VNI and VGI, respectively. A single active compound was further evaluated against C. neoformans genotypes VNII, VNIII, and VNIV, C. gattii genotypes VGI, VGIII, and VGIV, Candida albicans ATCC 36232, for cytotoxicity against the MRC-5 lineage of human fibroblasts and for effects on fungal cells (cell wall, ergosterol, and leakage of nucleic acids). E synthetic β-carboline 8-nitroharmane significantly inhibits pathogenic Cryptococcus species and is interesting as a lead compound towards new therapy for Cryptococcus infections Conclusions. e synthetic β-carboline 8-nitroharmane significantly inhibits pathogenic Cryptococcus species and is interesting as a lead compound towards new therapy for Cryptococcus infections
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