Advertisement

In Vitro Interaction of Geldanamycin with Triazoles and Echinocandins Against Common and Emerging Candida Species

  • Shahram Mahmoudi
  • Sassan Rezaie
  • Roshanak Daie Ghazvini
  • Seyed Jamal Hashemi
  • Hamid Badali
  • Alireza Foroumadi
  • Kambiz Diba
  • Anuradha Chowdhary
  • Jacques F. Meis
  • Sadegh KhodavaisyEmail author
Original Article

Abstract

The aim of this study was to determine the in vitro interactions of geldanamycin (Hsp90-inhibitor) with triazoles and echinocandins against common and emerging Candida species. Twenty clinically important Candida strains comprising C. auris, C. albicans, C. parapsilosis, and C. glabrata (each five strains) were included. In vitro interactions of geldanamycin with fluconazole, itraconazole, caspofungin and anidulafungin were determined using a checkerboard method. The results were interpreted as synergistic, indifferent and antagonistic based on the fractional inhibitory concentration index (FICI). In vitro combination of fluconazole with geldanamycin resulted in synergistic effect against C. albicans (100%), C. glabrata (80%) and C. parapsilosis (80%) (FICI range 0.009–0.5), while indifferent interactions were obtained against C. auris (FICI range 1.5–2). The overall minimum inhibitory concentration (MIC) range of fluconazole against C. albicans, C. glabrata and C. parapsilosis reduced from 16–256 to 0.25–64 mg/L when combined with geldanamycin. Regarding the synergistic effect of geldanamycin with itraconazole against all strains of C. albicans, C. glabrata and C. parapsilosis (FICI range 0.009–0.375), the MIC range of this antifungal was reduced from 0.125-32 mg/L when tested alone, to 0.03–1 mg/L. Combinations of geldanamycin with fluconazole and itraconazole against C. auris, as well as combination of geldanamycin with caspofungin and anidulafungin against all studied Candida species, resulted in indifferent effects. No antagonism was observed. Simultaneous targeting of Hsp90 and lanosterol 14-α demethylase seems an effective approach against C. albicans, C. glabrata and C. parapsilosis. However, this combination is ineffective against the emerging pathogen C. auris.

Keywords

Candida auris Drug synergism Drug interactions Drug resistance Hsp90 heat shock proteins 

Notes

Acknowledgements

The authors would like to thank Dr. Hossein Zarrinfar for his assistance during the study.

Funding

This work was financially supported by Tehran University of Medical Sciences, Tehran, Iran (Grant No. 9421353001).

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

Not applicable.

References

  1. 1.
    Rodrigues ME, Silva S, Azeredo J, Henriques M. Novel strategies to fight Candida species infection. Crit Rev Microbiol. 2016;42(4):594–606.Google Scholar
  2. 2.
    Sular FL, Szekely E, Cristea VC, Dobreanu M. Invasive fungal infection in Romania: changing incidence and epidemiology during six years of surveillance in a tertiary hospital. Mycopathologia. 2018;183(6):967–72.CrossRefGoogle Scholar
  3. 3.
    Whaley SG, Berkow EL, Rybak JM, et al. Azole antifungal resistance in Candida albicans and emerging non-albicans Candida species. Front Microbiol. 2017;7:2173.CrossRefGoogle Scholar
  4. 4.
    Asadzadeh M, Ahmad S, Al-Sweih N, et al. High-resolution fingerprinting of Candida parapsilosis isolates suggests persistence and transmission of infections among neonatal intensive care unit patients in Kuwait. Sci Rep. 2019;9(1):1340.CrossRefGoogle Scholar
  5. 5.
    Chowdhary A, Prakash A, Sharma, C et al. A multicentre study of antifungal susceptibility patterns among 350 Candida auris isolates (2009–17) in India: role of the ERG11 and FKS1 genes in azole and echinocandin resistance. J Antimicrob Chemother. 2018;73(4):891–899CrossRefGoogle Scholar
  6. 6.
    Roemer T, Krysan DJ. Antifungal drug development: challenges, unmet clinical needs, and new approaches. Cold Spring Harb Perspect Med. 2014;4(5):a019703.CrossRefGoogle Scholar
  7. 7.
    Gonçalves SS, Souza ACR, Chowdhary A, Meis JF, Colombo AL. Epidemiology and molecular mechanisms of antifungal resistance in Candida and Aspergillus. Mycoses. 2016;59(4):198–219.CrossRefGoogle Scholar
  8. 8.
    Spitzer M, Robbins N, Wright GD. Combinatorial strategies for combating invasive fungal infections. Virulence. 2017;8(2):169–85.CrossRefGoogle Scholar
  9. 9.
    Denardi LB, Keller JT, Oliveira V, et al. Activity of combined antifungal agents against multidrug-resistant Candida glabrata strains. Mycopathologia. 2017;182(9–10):819–28.CrossRefGoogle Scholar
  10. 10.
    Cowen LE, Lindquist S. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science. 2005;309(5744):2185–9.CrossRefGoogle Scholar
  11. 11.
    Zhang J, Liu W, Tan J, et al. Antifungal activity of geldanamycin alone or in combination with fluconazole against Candida species. Mycopathologia. 2013;175(3–4):273–9.CrossRefGoogle Scholar
  12. 12.
    Robbins N, Uppuluri P, Nett J, et al. Hsp90 governs dispersion and drug resistance of fungal biofilms. PLoS Pathog. 2011;7(9):e1002257.CrossRefGoogle Scholar
  13. 13.
    Matthews RC, Rigg G, Hodgetts S, et al. Preclinical assessment of the efficacy of mycograb, a human recombinant antibody against fungal HSP90. Antimicrob Agents Chemother. 2003;47(7):2208–16.CrossRefGoogle Scholar
  14. 14.
    Lamoth F, Juvvadi PR, Gehrke C, Steinbach WJ. In vitro activity of calcineurin and heat shock protein 90 inhibitors against Aspergillus fumigatus azole-and echinocandin-resistant strains. Antimicrob Agents Chemother. 2013;57(2):1035–9.CrossRefGoogle Scholar
  15. 15.
    Shirazi F, Kontoyiannis DP. Heat shock protein 90 and calcineurin pathway inhibitors enhance the efficacy of triazoles against Scedosporium prolificans via induction of apoptosis. Microb Cell. 2014;1(6):179–88.CrossRefGoogle Scholar
  16. 16.
    Lamoth F, Alexander BD, Juvvadi PR, Steinbach WJ. Antifungal activity of compounds targeting the Hsp90-calcineurin pathway against various mould species. J Antimicrob Chemother. 2015;70(5):1408–11.CrossRefGoogle Scholar
  17. 17.
    Clinical and Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing of yeasts; Fourth Informational Supplement. CLSI document M27-S4. Wayne, 2012.Google Scholar
  18. 18.
    CDC Recommendations for Antifungal Susceptibility Testing of Candida auris and Interpretation of results [cited 2019 3 January]. https://www.cdc.gov/fungal/candida-auris/c-auris-antifungal.html.
  19. 19.
    Odds FC. Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob Chemother. 2003;52(1):1–1.CrossRefGoogle Scholar
  20. 20.
    Arendrup MC, Patterson TF. Multidrug-resistant Candida: epidemiology, molecular mechanisms, and treatment. J Infect Dis. 2017;216(suppl_3):445–51.CrossRefGoogle Scholar
  21. 21.
    Perlin DS, Rautemaa-Richardson R, Alastruey-Izquierdo A. The global problem of antifungal resistance: prevalence, mechanisms, and management. Lancet Infect Dis. 2017;17(12):e383–92.CrossRefGoogle Scholar
  22. 22.
    Bastidas RJ, Reedy JL, Morales-Johansson H, Heitman J, Cardenas ME. Signaling cascades as drug targets in model and pathogenic fungi. Curr Opin Investig Drugs. 2008;9(8):856–64.Google Scholar
  23. 23.
    Wirk B. Heat shock protein inhibitors for the treatment of fungal infections. Recent Pat Antiinfect Drug Discov. 2011;6(1):38–44.CrossRefGoogle Scholar
  24. 24.
    Leach MD, Klipp E, Cowen LE, Brown AJ. Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs. Nat Rev Microbiol. 2012;10(10):693–704.CrossRefGoogle Scholar
  25. 25.
    Pachl J, Svoboda P, Jacobs F, et al. A randomized, blinded, multicenter trial of lipid-associated amphotericin B alone versus in combination with an antibody-based inhibitor of heat shock protein 90 in patients with invasive candidiasis. Clin Infect Dis. 2006;42(10):1404–13.CrossRefGoogle Scholar
  26. 26.
    Sidera K, Patsavoudi E. HSP90 inhibitors: current development and potential in cancer therapy. Recent Pat Anticancer Drug Discov. 2014;9(1):1–20.CrossRefGoogle Scholar
  27. 27.
    Gorska M, Popowska U, Sielicka-Dudzin A, et al. Geldanamycin and its derivatives as Hsp90 inhibitors. Front Biosci (Landmark Ed). 2012;17:2269–77.CrossRefGoogle Scholar
  28. 28.
    Kim SH, Iyer KR, Pardeshi L, et al. Genetic analysis of Candida auris implicates Hsp90 in morphogenesis and azole tolerance and CDR1 in azole resistance. mBio. 2019;10(1):e02529-18.CrossRefGoogle Scholar
  29. 29.
    O’Meara TR, Robbins N, Cowen LE. The Hsp90 chaperone network modulates Candida virulence traits. Trends Microbiol. 2017;25(10):809–19.CrossRefGoogle Scholar
  30. 30.
    Jhaveri K, Modi, S, HSP90 inhibitors for cancer therapy and overcoming drug resistance. In: Advances in pharmacology. 2012, Elsevier. p. 471–517.Google Scholar
  31. 31.
    Schopf FH, Biebl MM, Buchner J. The HSP90 chaperone machinery. Nat Rev Mol Cell Biol. 2017;18(6):345–60.CrossRefGoogle Scholar
  32. 32.
    Whitesell L, Robbins N, Huang DS, et al. Structural basis for species-selective targeting of Hsp90 in a pathogenic fungus. Nat Commun. 2019;10(1):402.CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Shahram Mahmoudi
    • 1
    • 2
  • Sassan Rezaie
    • 1
  • Roshanak Daie Ghazvini
    • 1
  • Seyed Jamal Hashemi
    • 1
    • 3
  • Hamid Badali
    • 4
  • Alireza Foroumadi
    • 5
  • Kambiz Diba
    • 6
  • Anuradha Chowdhary
    • 7
  • Jacques F. Meis
    • 8
    • 9
  • Sadegh Khodavaisy
    • 1
    Email author
  1. 1.Department of Medical Parasitology and Mycology, School of Public HealthTehran University of Medical SciencesTehranIran
  2. 2.Students’ Scientific Research CenterTehran University of Medical SciencesTehranIran
  3. 3.Food Microbiology Research CenterTehran University of Medical SciencesTehranIran
  4. 4.Department of Medical Mycology /Invasive Fungi Research Center, School of MedicineMazandaran University of Medical SciencesSariIran
  5. 5.Department of Medicinal Chemistry, Faculty of Pharmacy and The Institute of Pharmaceutical Sciences (TIPS)Tehran University of Medical SciencesTehranIran
  6. 6.Department of Medical Parasitology and Mycology, Faculty of MedicineUrmia University of Medical SciencesUrmiaIran
  7. 7.Department of Medical Mycology, Vallabhbhai Patel Chest InstituteUniversity of DelhiDelhiIndia
  8. 8.Center of Expertise in MycologyRadboud University Medical Centre/Canisius Wilhelmina Hospital and Excellence Center for Medical Mycology of the European Confederation of Medical Mycology (ECMM)NijmegenThe Netherlands
  9. 9.Department of Medical Microbiology and Infectious DiseasesCanisius Wilhelmina HospitalNijmegenNetherlands

Personalised recommendations