title: Inhibition of heat-shock protein 90 enhances the susceptibility to antifungals and reduces the virulence of Cryptococcus neoformans/Cryptococcus gattii species complex.
abstract: Heat-shock proteins (Hsps) are chaperones required for the maintenance of cellular homeostasis in different fungal pathogens, playing an important role in the infectious process. This study investigated the effect of pharmacological inhibition of Hsp90 by radicicol on the Cryptococcus neoformans/Cryptococcus gattii species complex--agents of the most common life-threatening fungal infection amongst immunocompromised patients. The influence of Hsp90 inhibition was investigated regarding in vitro susceptibility to antifungal agents of planktonic and sessile cells, ergosterol concentration, cell membrane integrity, growth at 37 °C, production of virulence factors in vitro, and experimental infection in Caenorhabditis elegans. Hsp90 inhibition inhibited the in vitro growth of planktonic cells of Cryptococcus spp. at concentrations ranging from 0.5 to 2 μg ml(-1) and increased the in vitro inhibitory effect of azoles, especially fluconazole (FLC) (P < 0.05). Inhibition of Hsp90 also increased the antifungal activity of azoles against biofilm formation and mature biofilms of Cryptococcus spp., notably for Cryptococcus gattii. Furthermore, Hsp90 inhibition compromised the permeability of the cell membrane, and reduced planktonic growth at 37 °C and the capsular size of Cryptococcus spp. In addition, Hsp90 inhibition enhanced the antifungal activity of FLC during experimental infection using Caenorhabditis elegans. Therefore, our results indicate that Hsp90 inhibition can be an important strategy in the development of new antifungal drugs.
authors.affiliation: Specialized Medical Mycology Center,Federal University of Ceará,Fortaleza, CE, Brazil.|Postgraduate Program in Medical Sciences,Federal University of Ceará, Fortaleza, CE,Brazil.|Postgraduate Program in Medical Microbiology,Federal University of Ceará, Fortaleza, CE,Brazil.
authors.forename: Rossana de Aguiar
authors.initials: RA
authors.lastname: Cordeiro
authors.affiliation: Specialized Medical Mycology Center,Federal University of Ceará,Fortaleza, CE, Brazil.|Postgraduate Program in Medical Sciences,Federal University of Ceará, Fortaleza, CE,Brazil.
authors.forename: Antonio José de Jesus
authors.initials: AJJ
authors.lastname: Evangelista
authors.affiliation: Specialized Medical Mycology Center,Federal University of Ceará,Fortaleza, CE, Brazil.|Postgraduate Program in Medical Microbiology,Federal University of Ceará, Fortaleza, CE,Brazil.
authors.forename: Rosana
authors.initials: R
authors.lastname: Serpa
authors.affiliation: Specialized Medical Mycology Center,Federal University of Ceará,Fortaleza, CE, Brazil.|Postgraduate Program in Medical Microbiology,Federal University of Ceará, Fortaleza, CE,Brazil.
authors.forename: Francisca Jakelyne de Farias
authors.initials: FJF
authors.lastname: Marques
authors.affiliation: Specialized Medical Mycology Center,Federal University of Ceará,Fortaleza, CE, Brazil.|Postgraduate Program in Medical Microbiology,Federal University of Ceará, Fortaleza, CE,Brazil.
authors.forename: Charlline Vládia Silva de
authors.initials: CVS
authors.lastname: Melo
authors.affiliation: Specialized Medical Mycology Center,Federal University of Ceará,Fortaleza, CE, Brazil.|Postgraduate Program in Medical Microbiology,Federal University of Ceará, Fortaleza, CE,Brazil.
authors.forename: Jonathas Sales de
authors.initials: JS
authors.lastname: Oliveira
authors.affiliation: Specialized Medical Mycology Center,Federal University of Ceará,Fortaleza, CE, Brazil.
authors.forename: Jônatas da Silva
authors.initials: JDS
authors.lastname: Franco
authors.affiliation: Specialized Medical Mycology Center,Federal University of Ceará,Fortaleza, CE, Brazil.|Postgraduate Program in Veterinary Sciences,State University of Ceará, Fortaleza, CE,Brazil.
authors.forename: Lucas Pereira de
authors.initials: LP
authors.lastname: Alencar
authors.affiliation: Specialized Medical Mycology Center,Federal University of Ceará,Fortaleza, CE, Brazil.|School of Medicine, Christus College - UNICHRISTUS,Fortaleza, CE,Brazil.
authors.forename: Tereza de Jesus Pinheiro Gomes
authors.initials: TJPG
authors.lastname: Bandeira
authors.affiliation: Specialized Medical Mycology Center,Federal University of Ceará,Fortaleza, CE, Brazil.|Postgraduate Program in Medical Sciences,Federal University of Ceará, Fortaleza, CE,Brazil.|Postgraduate Program in Medical Microbiology,Federal University of Ceará, Fortaleza, CE,Brazil.
authors.forename: Raimunda Sâmia Nogueira
authors.initials: RSN
authors.lastname: Brilhante
authors.affiliation: Specialized Medical Mycology Center,Federal University of Ceará,Fortaleza, CE, Brazil.|Postgraduate Program in Medical Sciences,Federal University of Ceará, Fortaleza, CE,Brazil.|Postgraduate Program in Medical Microbiology,Federal University of Ceará, Fortaleza, CE,Brazil.
authors.forename: José Júlio Costa
authors.initials: JJC
authors.lastname: Sidrim
authors.affiliation: Specialized Medical Mycology Center,Federal University of Ceará,Fortaleza, CE, Brazil.|Postgraduate Program in Medical Microbiology,Federal University of Ceará, Fortaleza, CE,Brazil.|Postgraduate Program in Veterinary Sciences,State University of Ceará, Fortaleza, CE,Brazil.
authors.forename: Marcos Fébio Gadelha
authors.initials: MFG
authors.lastname: Rocha
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development*; D017173:Caenorhabditis elegans / Q000382:microbiology*; D002462:Cell Membrane / Q000187:drug effects; D003453:Cryptococcosis / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D056285:Cryptococcus gattii / Q000254:growth & development / Q000472:pathogenicity*; D003455:Cryptococcus neoformans / Q000254:growth & development / Q000472:pathogenicity*; D004875:Ergosterol / Q000378:metabolism; D015725:Fluconazole / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology; D008543:Melanins / Q000096:biosynthesis; D008826:Microbial Sensitivity Tests; D010933:Plankton / Q000187:drug effects*; D065819:Voriconazole / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D018841:HSP90 Heat-Shock Proteins; D008543:Melanins; D017964:Itraconazole; D000666:Amphotericin B; D015725:Fluconazole; D065819:Voriconazole; D004875:Ergosterol