Melanins Protect Sporothrix brasiliensis and Sporothrix schenckii from the Antifungal Effects of Terbinafine

PLoS One. 2016 Mar 31;11(3):e0152796. doi: 10.1371/journal.pone.0152796. eCollection 2016.

Abstract

Terbinafine is a recommended therapeutic alternative for patients with sporotrichosis who cannot use itraconazole due to drug interactions or side effects. Melanins are involved in resistance to antifungal drugs and Sporothrix species produce three different types of melanin. Therefore, in this study we evaluated whether Sporothrix melanins impact the efficacy of antifungal drugs. Minimal inhibitory concentrations (MIC) and minimal fungicidal concentrations (MFC) of two Sporothrix brasiliensis and four Sporothrix schenckii strains grown in the presence of the melanin precursors L-DOPA and L-tyrosine were similar to the MIC determined by the CLSI standard protocol for S. schenckii susceptibility to amphotericin B, ketoconazole, itraconazole or terbinafine. When MICs were determined in the presence of inhibitors to three pathways of melanin synthesis, we observed, in four strains, an increase in terbinafine susceptibility in the presence of tricyclazole, a DHN-melanin inhibitor. In addition, one S. schenckii strain grown in the presence of L-DOPA had a higher MFC value when compared to the control. Growth curves in presence of 2×MIC concentrations of terbinafine showed that pyomelanin and, to a lesser extent, eumelanin were able to protect the fungi against the fungicidal effect of this antifungal drug. Our results suggest that melanin protects the major pathogenic species of the Sporothrix complex from the effects of terbinafine and that the development of new antifungal drugs targeting melanin synthesis may improve sporotrichosis therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antifungal Agents / pharmacology*
  • Humans
  • Melanins / metabolism*
  • Naphthalenes / pharmacology*
  • Sporothrix / drug effects*
  • Sporothrix / metabolism
  • Sporotrichosis / drug therapy*
  • Sporotrichosis / microbiology
  • Terbinafine
  • Thiazoles / pharmacology

Substances

  • Antifungal Agents
  • Melanins
  • Naphthalenes
  • Thiazoles
  • pyomelanin
  • eumelanin
  • Terbinafine
  • tricyclazole

Grants and funding

This work was supported by Programa institucional de indução à ciência, tecnologia e inovação em saúde PAPES VI – CNPq/Fiocruz (grant number 407693/2012-2), Conselho Nacional de desenvolvimento Científico e Tecnológico (grant numbers 304976/2013-0 to RMZ-O, and 449184/2014-5 to RA-P), and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (grant number E-26/103.157/2011 to RMZ-O). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.