title: Activation of Melanin Synthesis in Alternaria infectoria by Antifungal Drugs.
abstract: The importance of Alternaria species fungi to human health ranges from their role as etiological agents of serious infections with poor prognoses in immunosuppressed individuals to their association with respiratory allergic diseases. The present work focuses on Alternaria infectoria, which was used as a model organism of the genus, and was designed to unravel melanin production in response to antifungals. After we characterized the pigment produced by A. infectoria, we studied the dynamics of 1,8-dihydroxynaphthalene (DHN)-melanin production during growth, the degree of melanization in response to antifungals, and how melanization affected susceptibility to several classes of therapeutic drugs. We demonstrate that A. infectoria increased melanin deposition in cell walls in response to nikkomycin Z, caspofungin, and itraconazole but not in response to fluconazole or amphotericin B. These results indicate that A. infectoria activates DHN-melanin synthesis in response to certain antifungal drugs, possibly as a protective mechanism against these drugs. Inhibition of DHN-melanin synthesis by pyroquilon resulted in a lower minimum effective concentration (MEC) of caspofungin and enhanced morphological changes (increased hyphal balloon size), characterized by thinner and less organized A. infectoria cell walls. In summary, A. infectoria synthesizes melanin in response to certain antifungal drugs, and its susceptibility is influenced by melanization, suggesting the therapeutic potential of drug combinations that affect melanin synthesis.
authors.affiliation: CNC-Centre for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Chantal
authors.initials: C
authors.lastname: Fernandes
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, New York, USA CIC bioGUNE, Derio, Bizkaia, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Prados-Rosales
authors.affiliation: CNC-Centre for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Branca M A
authors.initials: BM
authors.lastname: Silva
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, New York, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Nakouzi-Naranjo
authors.affiliation: Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal FMUC-Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Mónica
authors.initials: M
authors.lastname: Zuzarte
authors.affiliation: Department of Chemistry, City College of New York, Graduate Center, and Institute for Macromolecular Assemblies, City University of New York, New York, New York, USA.
authors.forename: Subhasish
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Department of Chemistry, City College of New York, Graduate Center, and Institute for Macromolecular Assemblies, City University of New York, New York, New York, USA.
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Stark
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Arturo
authors.initials: A
authors.lastname: Casadevall
authors.affiliation: CNC-Centre for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal FMUC-Faculty of Medicine, University of Coimbra, Coimbra, Portugal tgoncalves@fmed.uc.pt.
authors.forename: Teresa
authors.identifier: http://orcid.org/0000-0001-9347-0535
authors.initials: T
authors.lastname: Gonçalves
mesh_terms: D000528:Alternaria / Q000187:drug effects*; D000617:Aminoglycosides / Q000494:pharmacology; D000666:Amphotericin B / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D000077336:Caspofungin; D002473:Cell Wall / Q000187:drug effects*; D054714:Echinocandins / Q000494:pharmacology; D015725:Fluconazole / Q000494:pharmacology; D017964:Itraconazole / Q000494:pharmacology; D055666:Lipopeptides / Q000494:pharmacology; D008543:Melanins / Q000096:biosynthesis*; D008826:Microbial Sensitivity Tests; D009284:Naphthols; D011758:Pyrroles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology
chemical_list: C423455:1,8-dihydroxynaphthalene melanin; D000617:Aminoglycosides; D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D008543:Melanins; D009284:Naphthols; D011758:Pyrroles; D011804:Quinolines; D017964:Itraconazole; D000666:Amphotericin B; D015725:Fluconazole; C011952:nikkomycin; D000077336:Caspofungin; C436408:pyroquilon