title: In vitro antifungal activity of miltefosine and levamisole: their impact on ergosterol biosynthesis and cell permeability of dimorphic fungi.
abstract: OBJECTIVE
  This study aimed to evaluate the in vitro activity of miltefosine and levamisole against strains of Coccidioides posadasii in the filamentous phase and strains of Histoplasma capsulatum in filamentous and yeast phases.
  
  
  RESULTS
  Strains of C. posadasii in the filamentous phase (n = 22) and strains of H. capsulatum in filamentous (n = 40) and yeast phases (n = 13) were, respectively, submitted to broth macrodilution and broth microdilution methods, as described by the Clinical and Laboratory Standards Institute, to determine the minimum inhibitory concentration (MIC) and the minimum fungicidal concentration (MFC) of miltefosine and levamisole. The effect of the drugs on cell membrane permeability under osmotic stress conditions and total ergosterol production were also assessed, along with quantification of extravasated molecules. The results show the inhibitory effect of levamisole and miltefosine against C. posadasii and H. capsulatum and the effect of these drugs on ergosterol synthesis and the permeability of the plasma membrane using subinhibitory concentrations against strains subjected to osmotic stress. Levamisole was also able to cause the release of nucleic acids.
  
  
  CONCLUSIONS
  Miltefosine and levamisole are capable of inhibiting the in vitro growth of C. posadasii and H. capsulatum, probably by altering the permeability of the cellular membrane.
  
  
  CONCLUSIONS
  This work presents alternatives for the treatment of histoplasmosis and coccidioidomycosis, raising the possibility of the use of miltefosine and levamisole as adjuvants in antifungal therapy, providing perspectives for the design of in vivo studies.
authors.affiliation: Specialized Medical Mycology Center, Postgraduate Program in Medical Microbiology, Federal University of Ceará, Fortaleza, CE, Brazil.|Postgraduate Program in Medical Sciences, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: R S N
authors.initials: RS
authors.lastname: Brilhante
authors.affiliation: Specialized Medical Mycology Center, Postgraduate Program in Medical Microbiology, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: E P
authors.initials: EP
authors.lastname: Caetano
authors.affiliation: Specialized Medical Mycology Center, Postgraduate Program in Medical Microbiology, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: R A C
authors.initials: RA
authors.lastname: Lima
authors.affiliation: Specialized Medical Mycology Center, Postgraduate Program in Medical Microbiology, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: D S C M
authors.initials: DS
authors.lastname: Castelo Branco
authors.affiliation: Specialized Medical Mycology Center, Postgraduate Program in Medical Microbiology, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: R
authors.initials: R
authors.lastname: Serpa
authors.affiliation: Specialized Medical Mycology Center, Postgraduate Program in Medical Microbiology, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: J S
authors.initials: JS
authors.lastname: Oliveira
authors.affiliation: Department of Statistics and Applied Mathematics, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: A J
authors.initials: AJ
authors.lastname: Monteiro
authors.affiliation: Specialized Medical Mycology Center, 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: M F G
authors.initials: MF
authors.lastname: Rocha
authors.affiliation: Specialized Medical Mycology Center, Postgraduate Program in Medical Microbiology, Federal University of Ceará, Fortaleza, CE, Brazil.|Postgraduate Program in Medical Sciences, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: R A
authors.initials: RA
authors.lastname: Cordeiro
authors.affiliation: Specialized Medical Mycology Center, Postgraduate Program in Medical Microbiology, Federal University of Ceará, Fortaleza, CE, Brazil.|Postgraduate Program in Medical Sciences, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: J J C
authors.initials: JJ
authors.lastname: Sidrim
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D003045:Coccidioides / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D004875:Ergosterol / Q000096:biosynthesis*; D006658:Histoplasma / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D007978:Levamisole / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D010767:Phosphorylcholine; D007978:Levamisole; C039128:miltefosine; D004875:Ergosterol
keywords: Coccidioides posadasii; Histoplasma capsulatum; antifungal activity; inhibitory effect; levamisole; miltefosine