Journal of Medical Microbiology Papers in Press. Published February 5, 2015 as doi:10.1099/jmm.0.000030
Journal of Medical Microbiology Histoplasma capsulatum in planktonic and biofilm forms: in vitro susceptibility to amphotericin B, itraconazole and farnesol --Manuscript Draft-Manuscript Number:
Histoplasma capsulatum in planktonic and biofilm forms: in vitro susceptibility to amphotericin B, itraconazole and farnesol
Antifungal susceptibility of H. capsulatum biofilm
Antimicrobial agents and chemotherapy
Raimunda Sâmia Nogueira Brilhante Federal University of Ceará Fortaleza, BRAZIL
Order of Authors:
Raimunda Brilhante Rita Amanda Chaves de Lima Francisca Jakelyne de Farias Marques Natalya Fechine Silva Erica Pacheco Caetano Débora de Souza Collares Maia Castelo-Branco Tereza de Jesus Pinheiro Gomes Bandeira José Luciano Bezerra Moreira Rossana de Aguiar Cordeiro André Jalles Monteiro Zoilo Pires de Camargo José Júlio Costa Sidrim Marcos Fábio Gadelha Rocha
It is believed that most microbial infections are caused by pathogens organized in biofilms. Recently, it was shown that the dimorphic fungus Histoplasma capsulatum, estimated to be the most common cause of fungal respiratory diseases, is also able to form biofilm. Although the antifungal therapy commonly used is effective, refractory cases and recurrences have been reported. In the search for new compounds with antimicrobial activity, the sesquiterpene farnesol has gained prominence for its antifungal action. This study aimed to evaluate the in vitro susceptibility of H. capsulatum var. capsulatum to the antifungal agents itraconazole and amphotericin B and farnesol, alone and combined, as well as to determine the in vitro antifungal activity of these compounds against biofilms of this pathogen. The results show that farnesol has antifungal activity against H. capsulatum in the yeast and filamentous phases, with MIC values ranging from 0.0078 to 0.00312 µM. A synergistic effect (FICI ≤ 0.5) between itraconazole and farnesol was found against 100% and 83.3% of the isolates in yeast and mycelial forms, respectively, while synergism between amphotericin B and farnesol was only observed against 37.5% and 44.4% of the isolates in yeast and filamentous forms, respectively. Afterwards, the antifungal drugs and farnesol alone and the combination of itraconazole and farnesol were tested against mature biofilms of H. capsulatum, through XTT metabolic assay, and the isolated antifungal drugs showed lower antibiofilm activity, when compared to farnesol alone and farnesol combined with itraconazole.
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Journal of Medical Microbiology.
Title: Histoplasma capsulatum in planktonic and biofilm forms: in vitro susceptibility
to amphotericin B, itraconazole and farnesol
Authors and affiliations: Raimunda Sâmia Nogueira Brilhante1,2*, Rita Amanda
Chaves de Lima1, Francisca Jakelyne de Farias Marques1, Natalya Fechine Silva2, Érica
Pacheco Caetano1, Débora de Souza Collares Maia Castelo-Branco1, Tereza de Jesus
Pinheiro Gomes Bandeira1,4, José Luciano Bezerra Moreira1, Rossana de Aguiar
Cordeiro1, André Jalles Monteiro5, Zoilo Pires de Camargo6, José Júlio Costa Sidrim1,2,
Marcos Fábio Gadelha Rocha1,3.
Microbiology, Federal University of Ceará, Fortaleza, Ceará, Brazil
Fortaleza, Ceará, Brazil.
São Paulo, São Paulo, Brazil
Running Title: Antifungal susceptibility of H. capsulatum biofilm
*Corresponding Author: R.S.N. Brilhante. Rua Barão de Canindé, 210; Montese.
albicans biofilm formation by farnesol, a quorum-sensing molecule. Appl Environ
Microbiol. 68, 5459-63.
Verstrepen KJ & Klis FM. (2006). Flocculation, adhesion and biofilm formation in
yeasts. Mol Microbiol. 60, 5-15.
Wheat LJ, Connolly P, Smedema M & Rogers PD. (2009).Antifungal drug
resistance in histoplasmosis. In Antimicrobial Drug Resistance. pp. 987-992.
367 368 369 370
Figure 1. In vitro susceptibility of H. capsulatum biofilm to amphotericin B, itraconazole and farnesol alone and combined with itraconazole. The data represent the mean absorbance values and standard deviation obtained from six H. capsulatum strains in biofilm form, through the XTT metabolic assay.
Table 1. Minimum inhibitory concentrations of amphotericin, itraconazole and farnesol alone and in combination against strains of H. capsulatum var. capsulatum. Drugs Alone Histoplasma capsulatum Yeast form (8)a
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