Antifungal resistance on Sporothrix species: an overview

Abstract

Introduction

The treatment of human and animal sporotrichosis is often performed with antifungal agents; however, the emergence of antifungal-resistant strains of Sporothrix species has been reported. We aimed to discuss the ability of Sporothrix species in developing resistance to the conventional antifungals and mechanisms for this.

Methodology

Published data on databases (PubMed, Science Direct, Google Scholar) were investigated using a combination of keywords from 2008 to 2019 by the StArt tool.

Results

The minimal inhibitory concentrations values based on the Clinical and Laboratory Standards Institute (CLSI) from eight references were classified according to the epidemiological cutoff values in wild-type or non-wild-type strains. In this way, non-wild-type S. schenckii and, mainly, S. brasiliensis isolates were recognized on itraconazole, amphotericin B, terbinafine, and voriconazole, which are strains that deserve more attention toward antifungal control, with a probable risk of mutation to antifungal resistance. Among the few reviewed studied on antifungal resistance, the melanin production capacity (DHN-melanin, L-DOPA melanin, and pyomelanin), the low genetic diversity due to the abnormal number of chromosomes, and the mutation in cytochrome P450 are some of the factors for developing resistance mechanism.

Conclusions

The emergence of Sporothrix species with in vitro antifungal resistance was evidenced and the possible mechanisms for resistance development may be due to the melanin production capacity, genetic diversity and mutations in cytochrome P450. Further studies should be carried out targeting gene expression for the development of antifungal resistance on Sporothrix species in order to prospect new therapeutic targets for human and veterinary use.

This is a preview of subscription content, log in to check access.

Fig. 1

References

  1. 1.

    Fischman Gompertz O, Rodrigues AM, Fernandes GF, Bentubo HD, de Camargo ZP, Petri V (2016) Atypical clinical presentation of sporotrichosis caused by Sporothrix globosa resistant to itraconazole. Am J Trop Med Hyg 94:1218–1222. https://doi.org/10.4269/ajtmh.15-0267

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Vettorato R, Heidrich D, Fraga F, Ribeiro AC, Pagani DM, Timotheo C, Amaro TG, Vettorato G, Scroferneker ML (2017) Sporotrichosis by Sporothrix schenckii senso stricto with itraconazole resistance and terbinafine sensitivity observed in vitro and in vivo: case report. Med Mycol Case Rep 19:18–20. https://doi.org/10.1016/j.mmcr.2017.10.001

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Espinel-Ingroff A, Abreu DPB, Almeida-Paes R, Brilhante RSN, Chakrabarti A, Chowdhary A, Hagen F, Córdoba S, Gonzalez GM, Govender NP, Guarro J, Johnson EM, Kidd SE, Pereira SA, Rodrigues AM, Rozental S, Szeszs MW, Ballesté Alaniz R, Bonifaz A, Bonfietti LX, Borba-Santos LP, Capilla J, Colombo AL, Dolande M, Isla MG, Melhem MSC, Mesa-Arango AC, Oliveira MME, Panizo MM, Pires de Camargo Z, Zancope-Oliveira RM, Meis JF, Turnidge J (2017) International study of MIC/MEC distributions for definition of epidemiological cutoff values for Sporothrix species identified by molecular methods. Antimicrob Agents Chemother 61:e01057–e01017. https://doi.org/10.1128/AAC.01057-17

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Guterres KA, de Matos CB, Osório Lda G, Schuch ID, Cleff MB (2014) The use of (1-3) β-glucan along with itraconazole against canine refractory sporotrichosis. Mycopathologia 177:217–221. https://doi.org/10.1007/s11046-014-9736-6

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Rodrigues AM, Della Terra PP, Gremião ID, Pereira SA, Orofino-Costa R, de Camargo ZP (2020) The threat of emerging and re-emerging pathogenic Sporothrix species. Mycopathologia 1–30. https://doi.org/10.1007/s11046-020-00425-0

  6. 6.

    Orofino-Costa R, Macedo PM, Rodrigues AM, Bernardes-Engemann AR (2017) Sporotrichosis: an update on epidemiology, etiopathogenesis, laboratory and clinical therapeutics. An Bras Dermatol 92:606–620. https://doi.org/10.1590/abd1806-4841.2017279

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Govender NP, Maphanga TG, Zulu TG, Patel J (2015) An outbreak of Lymphocutaneous Sporotrichosis among mine-workers in South Africa. PLoS Negl Trop Dis 9:e0004096. https://doi.org/10.1371/journal.pntd.0004096

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Da Rocha RFDB, Schubach TMP, Pereira SA, dos Reis ÉG, Carvalho BW, Gremião IDF (2018) Refractory feline sporotrichosis treated with itraconazole combined with potassium iodide. J Small Anim Pract 59:720–721. https://doi.org/10.1111/jsap.12852

    Article  PubMed  Google Scholar 

  9. 9.

    Gremião I, Schubach T, Pereira S, Rodrigues A, Honse C, Barros M (2011) Treatment of refractory feline sporotrichosis with a combination of intralesional amphotericin B and oral itraconazole. Aust Vet J 89:346–351. https://doi.org/10.1111/j.1751-0813.2011.00804.x

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Clinical and Laboratory Standard Institute (2008) Reference method for broth dilution antifungal susceptibility testing of filamentous fungi: approved M38-a, 2nd edn. CLSI, Wayne, 52 pp

    Google Scholar 

  11. 11.

    Arendrup MC, Cuenca-Estrella M, Lass-Flörl C, Hope W, Howard SJ, the Subcommittee on Antifungal Susceptibility Testing (AFST) of the ESCMID European Committee for Antimicrobial Susceptibility Testing (EUCAST) (2015) Method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for conidia forming moulds. EUCAST Definitive Document EDef 9.2. European Society of Clinical Microbiology and Infectious Diseases, Taufkirchen 24 pp

    Google Scholar 

  12. 12.

    Rodrigues AM, de Hoog GS, de Cássia PD et al (2014) Genetic diversity and antifungal susceptibility profiles in causative agents of sporotrichosis. BMC Infect Dis 14:219. https://doi.org/10.1186/1471-2334-14-219

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Waller SB, Madrid IM, Hoffmann JF, Picoli T, Cleff MB, Chaves FC, Faria RO, Meireles MCA, Braga de Mello JR (2017) Chemical composition and cytotoxicity of extracts of marjoram and rosemary and their activity against Sporothrix brasiliensis. J Med Microbiol 66:1076–1083. https://doi.org/10.1099/jmm.0.000517

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Sanchotene KO, Brandolt TM, Klafke GB, Poester VR, Xavier MO (2017) In vitro susceptibility of Sporothrix brasiliensis: comparison of yeast and mycelial phases. Med Mycol 55:869–876. https://doi.org/10.1093/mmy/myw143

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Waller SB, Peter CM, Hoffmann JF, Picoli T, Osório LG, Chaves F, Zani JL, de Faria RO, de Mello JRB, Meireles MCA (2017) Chemical and cytotoxic analyses of brown Brazilian propolis (Apis mellifera) and its in vitro activity against itraconazole-resistant Sporothrix brasiliensis. Microb Pathog 105:117–121. https://doi.org/10.1016/j.micpath.2017.02.022

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Marimon R, Serena C, Gené J, Cano J, Guarro J (2008) In vitro antifungal susceptibilities of five species of Sporothrix. Antimicrob Agents Chemother 14:732–734. https://doi.org/10.1128/AAC.01012-07

    CAS  Article  Google Scholar 

  17. 17.

    Córdoba S, Isla G, Szusz W, Vivot W, Hevia A, Davel G, Canteros CE (2018) Molecular identification and susceptibility profile of Sporothrix schenckii sensu lato isolated in Argentina. Mycoses 61:441–448. https://doi.org/10.1111/myc.12760

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Brilhante RS, Rodrigues AM, Sidrim JJ et al (2016) In vitro susceptibility of antifungal drugs against Sporothrix brasiliensis recovered from cats with sporotrichosis in Brazil. Med Mycol 54:275–279. https://doi.org/10.1093/mmy/myv039

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Waller SB, Madrid IM, Silva AL, Dias de Castro LL, Cleff MB, Ferraz V, Meireles MCA, Zanette R, de Mello JRB (2016) In vitro susceptibility of Sporothrix brasiliensis to essential oils of Lamiaceae family. Mycopathologia 181:857–863. https://doi.org/10.1007/s11046-016-0047-y

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Stopiglia CDO, Magagnin CM, Castrillón MR et al (2014) Antifungal susceptibilities and identification of species of the Sporothrix schenckii complex isolated in Brazil. Med Mycol 52:56–64. https://doi.org/10.3109/13693786.2013.818726

    CAS  Article  Google Scholar 

  21. 21.

    Almeida-Paes R, Oliveira MME, Freitas DFS, do Valle ACF, Gutierrez-Galhardo MC, Zancope-Oliveira RM (2017) Refractory sporotrichosis due to Sporothrix brasiliensis in humans appears to be unrelated to in vivo resistance. Med Mycol 55:507–517. https://doi.org/10.1093/mmy/myw103

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Gutierrez-Galhardo MC, Zancopé-Oliveira RM, Monzón A, Rodriguez-Tudela JL, Cuenca-Estrella M (2010) Antifungal susceptibility profile in vitro of Sporothrix schenckii in two growth phases and by two methods: microdilution and E-test. Mycoses 53:227–231. https://doi.org/10.1111/j.1439-0507.2009.01701.x

    Article  PubMed  Google Scholar 

  23. 23.

    Wolff D, Feldt T, Reifenberger J, Sebald H, Bogdan C (2018) Closing the brief case: cutaneous Sporotrichosis in an Immunocompetent patient after travel to Peru. J Clin Microbiol 56:e01961–e01917. https://doi.org/10.1128/JCM.01961-17

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Almeida-Paes R, Frases S, Araújo GS et al (2012) Biosynthesis and functions of a melanoid pigment produced by species of the Sporothrix complex in the presence of L-tyrosine. Appl Environ Microbiol 78:8623–8630. https://doi.org/10.1128/AEM.02414-12

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Romero-Martinez R, Wheeler M, Guerrero-Plata A, Rico G, Torres-Guerrero H (2000) Biosynthesis and functions of melanin in Sporothrix schenckii. Infect Immun 68:3696–3703. https://doi.org/10.1128/IAI.68.6.3696-3703.2000

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Almeida-Paes R, Figueiredo-Carvalho MH, Brito-Santos F, Almeida-Silva F, Oliveira MM, Zancopé-Oliveira RM (2016) Melanins protect Sporothrix brasiliensis and Sporothrix schenckii from the antifungal effects of terbinafine. PLoS One 11:e0152796. https://doi.org/10.1371/journal.pone.0152796

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Tsai H, Wheeler MH, Chang YC, Chang YC, Kwon-Chung KJ (1999) A developmentally regulated gene cluster involved in conidial pigment biosynthesis in Aspergillus fumigatus. J Bacteriol 181:6469–6477

    CAS  Article  Google Scholar 

  28. 28.

    Teixeira MM, de Almeida LGP, Kubitschek-Barreira P, Alves FL, Kioshima ÉS, Abadio AKR, Fernandes L, Derengowski LS, Ferreira KS, Souza RC, Ruiz JC, de Andrade NC, Paes HC, Nicola AM, Albuquerque P, Gerber AL, Martins VP, Peconick LDF, Neto A, Chaucanez CB, Silva PA, Cunha OL, de Oliveira FFM, dos Santos TC, Barros ALN, Soares MA, de Oliveira LM, Marini MM, Villalobos-Duno H, Cunha MML, de Hoog S, da Silveira JF, Henrissat B, Niño-Vega GA, Cisalpino PS, Mora-Montes HM, Almeida SR, Stajich JE, Lopes-Bezerra LM, Vasconcelos ATR, Felipe MSS (2014) Comparative genomics of the major fungal agents of human and animal Sporotrichosis: Sporothrix schenckii and Sporothrix brasiliensis. BMC Genomics 15:1–22. https://doi.org/10.1186/1471-2164-15-943

    Article  Google Scholar 

  29. 29.

    De Oliveira MM, Veríssimo C, Sabino R et al (2014) First autochthone case of sporotrichosis by Sporothrix globosa in Portugal. Diagn Microbiol Infect Dis 78:388–390. https://doi.org/10.1016/j.diagmicrobio.2013.08.023

    Article  PubMed  Google Scholar 

  30. 30.

    Gong J, Zhang M, Wang Y, Li R, He L, Wan Z, Li F, Zhang J (2019) Population structure and genetic diversity of Sporothrix globosa in China according to 10 novel microsatellite loci. J Med Microbiol 68:248–254. https://doi.org/10.1099/jmm.0.000896

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Huang L, Gao W, Giosa D, Criseo G, Zhang J, He T, Huang X, Sun J, Sun Y, Huang J, Zhang Y, Brankovics B, Scordino F, D'Alessandro E, van Diepeningen A, de Hoog S, Huang H, Romeo O (2016) Whole-genome sequencing and in silico analysis of two strains of Sporothrix globosa. Genome Biol Evol 8:3292–3296. https://doi.org/10.1093/gbe/evw230

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Sasaki AA, Fernandes GF, Rodrigues AM, Lima FM, Marini MM, dos Feitosa LS, de Melo Teixeira M, Felipe MSS, da Silveira JF, de Camargo ZP (2014) Chromosomal polymorphism in the Sporothrix schenckii complex. PLoS One 14:e86819. https://doi.org/10.1371/journal.pone.0086819

    CAS  Article  Google Scholar 

  33. 33.

    Rodrigues AM, de Hoog GS, Zhang Y, Camargo ZP (2014) Emerging sporotrichosis is driven by clonal and recombinant Sporothrix species. Emerg Microbes Infect 3(5):e32. https://doi.org/10.1038/emi.2014.33

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Rodrigues AM, de Melo TM, de Hoog GS et al (2014) Phylogenetic analysis reveals a high prevalence of Sporothrix brasiliensis in feline sporotrichosis outbreaks. PLoS Negl Trop Dis 7(6):e2281. https://doi.org/10.1371/journal.pntd.0002281

    Article  Google Scholar 

  35. 35.

    Rangel-Gamboa L, Martínez-Hernandez F, Maravilla P, Arenas-Guzmán R, Flisser A (2016) Update of phylogenetic and genetic diversity of Sporothrix schenckii sensu lato. Med Mycol 54(3):248–255. https://doi.org/10.1093/mmy/myv096

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Fernandes GF, dos Santos PO, Rodrigues AM, Sasaki AA, Burger E, de Camargo ZP (2013) Characterization of virulence profile, protein secretion and immunogenicity of different Sporothrix schenckii sensu stricto isolates compared with S. globosa and S. brasiliensis species. Virulence 4:241–249. https://doi.org/10.4161/viru.23112

    Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Waller SB, Ripoll MK, Madrid IM, Acunha T, Cleff MB, Chaves FC, de Mello JRB, de Faria RO, Meireles MCA (2020) Susceptibility and resistance of Sporothrix brasiliensis to branded and compounded itraconazole formulations. Braz J Microbiol. https://doi.org/10.1007/s42770-020-00280-7

  38. 38.

    Harrison BD, Hashemi J, Bibi M, Pulver R, Bavli D, Nahmias Y, Wellington M, Sapiro G, Berman J (2014) A tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole. PLoS Biol 12:e1001815. https://doi.org/10.1371/journal.pbio.1001815

    Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Hill JA, Ammar R, Torti D, Nislow C, Cowen LE (2013) Genetic and genomic architecture of the evolution of resistance to antifungal drug combinations. PLoS Genet 9:e1003390. https://doi.org/10.1371/journal.pgen.1003390

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Ni M, Feretzaki M, Li W, Floyd-Averette A, Mieczkowski P, Dietrich FS, Heitman J (2013) Unisexual and heterosexual meiotic reproduction generate aneuploidy and phenotypic diversity de novo in the yeast Cryptococcus neoformans. PLoS Biol 11:e1001653. https://doi.org/10.1371/journal.pbio.1001653

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Kelly SL, Lamb DC, Corran AJ, Baldwin BC, Kelly DE (1995) Mode of action and resistance to azole antifungals associated with the formation of 14 alpha-methylergosta-8,24(28)-dien-3 beta,6 alpha-diol. Biochem Biophys Res Commun 207:910–915. https://doi.org/10.1006/bbrc.1995.1272

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Matowane RG, Wieteska L, Bamal HD, Kgosiemang IKR, van Wyk M, Manume NA, Abdalla SMH, Mashele SS, Gront D, Syed K (2018) In silico analysis of cytochrome P450 monooxygenases in chronic granulomatous infectious fungus Sporothrix schenckii: special focus on CYP51. Biochim Biophys Acta, Proteins Proteomics 1866:166–177. https://doi.org/10.1016/j.bbapap.2017.10.003

    CAS  Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Stefanie Bressan Waller.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

Not applicable. This paper does not contain any studies with experimental animals.

Informed consent

Not applicable. This paper does not contain any studies with human participants performed by any of the authors.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Responsible Editor: Sandro Rogerio de Almeida.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Waller, S.B., Dalla Lana, D.F., Quatrin, P.M. et al. Antifungal resistance on Sporothrix species: an overview. Braz J Microbiol (2020). https://doi.org/10.1007/s42770-020-00307-z

Download citation

Keywords

  • Sporotrichosis
  • Sporothrix species
  • Antifungal resistance
  • Melanin
  • Genetic diversity
  • Mutation
  • Gene expression