Screening and Antifungal Activity of a β-Carboline Derivative against Cryptococcus neoformans and C. gattii

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.

[1]  M. Dell’Agli,et al.  Bioprospecting on invasive plant species to prevent seed dispersal , 2017, Scientific Reports.

[2]  Bharat Rash,et al.  A Nonredundant Phosphopantetheinyl Transferase, PptA, Is a Novel Antifungal Target That Directs Secondary Metabolite, Siderophore, and Lysine Biosynthesis in Aspergillus fumigatus and Is Critical for Pathogenicity , 2017, mBio.

[3]  R. Bucki,et al.  Development of antifungal therapies using nanomaterials. , 2017, Nanomedicine.

[4]  E. Ceretti,et al.  A battery of assays as an integrated approach to evaluate fungal and mycotoxin inhibition properties and cytotoxic/genotoxic side-effects for the prioritization in the screening of thiosemicarbazone derivatives. , 2017, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[5]  C. Petosa,et al.  Selective BET bromodomain inhibition as an antifungal therapeutic strategy , 2017, Nature Communications.

[6]  J. Perfect.  The antifungal pipeline: a reality check , 2017, Nature Reviews Drug Discovery.

[7]  W. Powderly,et al.  Cryptococcosis Today: It Is Not All About HIV Infection , 2017, Current Clinical Microbiology Reports.

[8]  F. Cabrerizo,et al.  Antifungal activity of β-carbolines on Penicillium digitatum and Botrytis cinerea. , 2017, Food microbiology.

[9]  H. Shih,et al.  Disseminated Cryptococcosis Due to Anti-Granulocyte-Macrophage Colony-Stimulating Factor Autoantibodies in the Absence of Pulmonary Alveolar Proteinosis , 2016, Journal of Clinical Immunology.

[10]  Ignacio Moraleda,et al.  Harmaline and hispidin from Peganum harmala and Inonotus hispidus with binding affinity to Candida rugosa lipase: In silico and in vitro studies. , 2015, Bioorganic chemistry.

[11]  A. Idnurm,et al.  Rising to the challenge of multiple Cryptococcus species and the diseases they cause. , 2015, Fungal genetics and biology : FG & B.

[12]  J. V. B. Souza,et al.  Antifungal activity of synthetic naphthoquinones against dermatophytes and opportunistic fungi: preliminary mechanism-of-action tests , 2014, Annals of Clinical Microbiology and Antimicrobials.

[13]  Hongjian Song,et al.  Synthesis and antiviral and fungicidal activity evaluation of β-carboline, dihydro-β-carboline, tetrahydro-β-carboline alkaloids, and their derivatives. , 2014, Journal of agricultural and food chemistry.

[14]  L. Espinoza,et al.  Antifungal Activity of Eugenol Analogues. Influence of Different Substituents and Studies on Mechanism of Action , 2012, Molecules.

[15]  P. Vandeputte,et al.  Antifungal Resistance and New Strategies to Control Fungal Infections , 2011, International journal of microbiology.

[16]  Gomah E. Nenaah.  Antibacterial and antifungal activities of (beta)-carboline alkaloids of Peganum harmala (L) seeds and their combination effects. , 2010, Fitoterapia.

[17]  V. Arán,et al.  beta-Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO). , 2010, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[18]  J. Perfect,et al.  Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[19]  S. Zacchino,et al.  Evidence for the mechanism of action of the antifungal phytolaccoside B isolated from Phytolacca tetramera Hauman. , 2008, Journal of natural products.

[20]  Hadjiakhoondi Abbas,et al.  Cytotoxicity and Antimicrobial Activity of Harman Alkaloids , 2007 .

[21]  I. Kubo,et al.  Effect of Polygodial on the Mitochondrial ATPase of Saccharomyces cerevisiae , 2000, Antimicrobial Agents and Chemotherapy.

[22]  G R Nakayama,et al.  Assessment of the Alamar Blue assay for cellular growth and viability in vitro. , 1997, Journal of immunological methods.

[23]  D. Frost,et al.  A whole-cell Candida albicans assay for the detection of inhibitors towards fungal cell wall synthesis and assembly. , 1995, The Journal of antibiotics.

[24]  Clinical,et al.  Reference method for broth dilution antifungal susceptibility testing of yeasts : Approved standard , 2008 .

[25]  A. Ahmad,et al.  Study of the in vitro antimicrobial activity of harmine, harmaline and their derivatives. , 1992, Journal of ethnopharmacology.