title: Antifungal activity of naphthoquinoidal compounds in vitro against fluconazole-resistant strains of different Candida species: a special emphasis on mechanisms of action on Candida tropicalis.
abstract: In recent decades, the incidence of candidemia in tertiary hospitals worldwide has substantially increased. These infections are a major cause of morbidity and mortality; in addition, they prolong hospital stays and raise the costs associated with treatment. Studies have reported a significant increase in infections by non-albicans Candida species, especially C. tropicalis. The number of antifungal drugs on the market is small in comparison to the number of antibacterial agents available. The limited number of treatment options, coupled with the increasing frequency of cross-resistance, makes it necessary to develop new therapeutic strategies. The objective of this study was to evaluate and compare the antifungal activities of three semisynthetic naphthofuranquinone molecules against fluconazole-resistant Candida spp. strains. These results allowed to us to evaluate the antifungal effects of three naphthofuranquinones on fluconazole-resistant C. tropicalis. The toxicity of these compounds was manifested as increased intracellular ROS, which resulted in membrane damage and changes in cell size/granularity, mitochondrial membrane depolarization, and DNA damage (including oxidation and strand breakage). In conclusion, the tested naphthofuranquinones (compounds 1-3) exhibited in vitro cytotoxicity against fluconazole-resistant Candida spp. strains.
authors.affiliation: Department of Clinical and Toxicological Analysis, School of Pharmacy, Laboratory of Bioprospection and Experiments in Yeast (LABEL), Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: João B A
authors.initials: JB
authors.lastname: Neto
authors.affiliation: Department of Clinical and Toxicological Analysis, School of Pharmacy, Laboratory of Bioprospection and Experiments in Yeast (LABEL), Federal University of Ceará, Fortaleza, Ceará, Brazil; Department of Pathology and Legal Medicine, School of Medicine, Laboratory of Bioprospection and Experiments in Yeast (LABEL), Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Cecília R
authors.initials: CR
authors.lastname: da Silva
authors.affiliation: Department of Clinical and Toxicological Analysis, School of Pharmacy, Laboratory of Bioprospection and Experiments in Yeast (LABEL), Federal University of Ceará, Fortaleza, Ceará, Brazil; Department of Pathology and Legal Medicine, School of Medicine, Laboratory of Bioprospection and Experiments in Yeast (LABEL), Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Maria A S
authors.initials: MA
authors.lastname: Neta
authors.affiliation: Department of Clinical and Toxicological Analysis, School of Pharmacy, Laboratory of Bioprospection and Experiments in Yeast (LABEL), Federal University of Ceará, Fortaleza, Ceará, Brazil; Department of Pathology and Legal Medicine, School of Medicine, Laboratory of Bioprospection and Experiments in Yeast (LABEL), Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Rosana S
authors.initials: RS
authors.lastname: Campos
authors.affiliation: Department of Clinical and Toxicological Analysis, School of Pharmacy, Laboratory of Bioprospection and Experiments in Yeast (LABEL), Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Janaína T
authors.initials: JT
authors.lastname: Siebra
authors.affiliation: Department of Clinical and Toxicological Analysis, School of Pharmacy, Laboratory of Bioprospection and Experiments in Yeast (LABEL), Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Rose A C
authors.initials: RA
authors.lastname: Silva
authors.affiliation: Department of Physiology and Pharmacology, Laboratory of Experimental Oncology, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Gaspar
authors.affiliation: Department of Clinical and Toxicological Analysis, School of Pharmacy, Laboratory of Bioprospection and Experiments in Yeast (LABEL), Federal University of Ceará, Fortaleza, Ceará, Brazil; Department of Pharmaceutical Sciences, Center for Toxicological Assistance, University Federal of Paraíba, Paraíba, Brazil.
authors.forename: Hemerson I F
authors.initials: HI
authors.lastname: Magalhães
authors.affiliation: Department of Physiology and Pharmacology, Laboratory of Experimental Oncology, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Manoel O
authors.initials: MO
authors.lastname: de Moraes
authors.affiliation: Department of Biology, ScienceCenter, Molecular Genetics Laboratory, Federal University of Ceará, Ceará, Brazil.
authors.forename: Marina D P
authors.initials: MD
authors.lastname: Lobo
authors.affiliation: Department of Biology, ScienceCenter, Molecular Genetics Laboratory, Federal University of Ceará, Ceará, Brazil.
authors.forename: Thalles B
authors.initials: TB
authors.lastname: Grangeiro
authors.affiliation: Natural Products Research Nucleus, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Tatiane S C
authors.initials: TS
authors.lastname: Carvalho
authors.affiliation: Department of Chemistry, Institute of Exact Sciences, Laboratory of Synthetic and Heterocyclic Chemistry, Federal University of Minas Gerais, Minas Gerais, Brazil.
authors.forename: Emilay B T
authors.initials: EB
authors.lastname: Diogo
authors.affiliation: Department of Chemistry, Institute of Exact Sciences, Laboratory of Synthetic and Heterocyclic Chemistry, Federal University of Minas Gerais, Minas Gerais, Brazil.
authors.forename: Eufrânio N
authors.initials: EN
authors.lastname: da Silva Júnior
authors.affiliation: Department of Physiology and Pharmacology, Laboratory of Experimental Oncology, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Felipe A R
authors.initials: FA
authors.lastname: Rodrigues
authors.affiliation: Department of Pathology and Legal Medicine, School of Medicine, Laboratory of Bioprospection and Experiments in Yeast (LABEL), Federal University of Ceará, Fortaleza, Ceará, Brazil; Department of Physiology and Pharmacology, Laboratory of Experimental Oncology, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Cavalcanti
authors.affiliation: Department of Clinical and Toxicological Analysis, School of Pharmacy, Laboratory of Bioprospection and Experiments in Yeast (LABEL), Federal University of Ceará, Fortaleza, Ceará, Brazil; Department of Pathology and Legal Medicine, School of Medicine, Laboratory of Bioprospection and Experiments in Yeast (LABEL), Federal University of Ceará, Fortaleza, Ceará, Brazil; Department of Physiology and Pharmacology, Laboratory of Experimental Oncology, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Hélio V N
authors.initials: HV
authors.lastname: Júnior
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002175:Candida / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D041022:Candida tropicalis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004271:DNA, Fungal / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D021903:DNA, Ribosomal Spacer / Q000737:chemistry / Q000235:genetics; D025141:Drug Resistance, Fungal / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D015725:Fluconazole / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010718:Phosphatidylserines; D012340:RNA, Ribosomal, 5.8S / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D000935:Antifungal Agents; D004271:DNA, Fungal; D021903:DNA, Ribosomal Spacer; D009285:Naphthoquinones; D010718:Phosphatidylserines; D012340:RNA, Ribosomal, 5.8S; D017382:Reactive Oxygen Species; D015725:Fluconazole