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Synergy In Vitro of Nikkomycin Z with Azole Against the Invasive Form of Candida albicans

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Abstract

In a previous study, therapeutic activity of nikkomycin Z (NZ) in a model of invasive candidiasis did not appear to correlate with lesser activity in vitro (using classical MIC methods) with planktonic organisms. However, NZ potency was much greater assaying activity in vitro against germ tubes, the initiator of the invasive mycelial form of the fungus, as occurs in infected tissues. Synergy has been demonstrated for NZ and other drugs, notably fluconazole (the most commonly used drug against candidiasis), in planktonic testing, which correlated with results in vivo. This raised the question whether activity shown by NZ alone against germ tubes would be reflected in drug combinations, and even whether synergy testing against germ tubes might be a better correlate of synergy in future in vivo studies. We show in this study significant NZ synergy with fluconazole against germ tubes, for several C. albicans isolates, with testing in many drug ratios. This observation opens the way for further explorations of this method of susceptibility testing for synergy, and correlation with combination therapy against candidiasis.

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Abbreviations

NZ:

Nikkomycin Z

FCZ:

Fluconazole

IC50:

50% Inhibitory concentration

MIC:

Minimum inhibitory concentration in planktonic assays

References

  1. Fiedler H-P, Schuz T, Decker H. An overview of nikkomycins: history, biochemistry, and applications. In: Rippon JW, Fromtling RA, editors. Cutaneous antifungal agents. New York: Marcel Dekker Inc.; 1993. p. 325–52.

    Google Scholar 

  2. Sass G, Larwood DJ, Martinez M, Stevens DA. Continuous dosing of nikkomycin Z against systemic candidiasis, in vivo and in vitro correlates. Mycoses. 2023. https://doi.org/10.1111/myc.13569.

    Article  PubMed  Google Scholar 

  3. Barnes JL, Osgood RW, Lee JC, King RD, Stein JH. Host-parasite interactions in the pathogenesis of experimental renal candidiasis. Lab Invest. 1983;49:460–7.

    CAS  PubMed  Google Scholar 

  4. Ryley JF, Ryley NG. Candida albicans- do mycelia matter? J Med Vet Mycol. 1990;28:225–9.

    Article  CAS  PubMed  Google Scholar 

  5. Milewski S, Mignini F, Borowski E. Synergistic action of nikkomycin X/Z with azole antifungals on Candida albicans. J Gen Micro. 1991;137:2155–61.

    Article  CAS  Google Scholar 

  6. Li RK, Rinaldi MG. In vitro antifungal activity of Nikkomycin Z in combination with fluconazole or itraconazole. Antimicrob Agents Chemother. 1999;43:1401–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kim N-K, Park H-S, Kim C-H, Park H-M, Choi W. Inhibitory effect of nikkomycin Z on chitin synthases in Candida albicans. Yeast. 2002;19:341–9.

    Article  CAS  PubMed  Google Scholar 

  8. Hector RF, Schaller K. Positive interaction of nikkomycins and azoles against Candida albicans in vitro and in vivo. Antimicrob Agents Chemother. 1992;36:1284–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Andes DR, Safdar N, Baddley JW, Playford G, Reboli AC, Rex JH, Sobel JD, Pappas PG, Kullberg BJ; Mycoses Study Group. Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis. 2012;54:1110–22.

  10. Clemons KV, Gonzalez GM, Singh G, Imai J, Espiritu M, Parmar R, Stevens DA. Development of an orogastrointestinal mouse model of candidiasis with dissemination to visceral organs. Antimicrob Agents Chemother. 2006;50:2650–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. CLSI. Reference method for broth dilution antifungal susceptibility testing of yeasts—4th Edition: M27. Malvern: CLSI pub.; 2017.

  12. Sabath LD, Lorian V. In vitro tests for antibacterial activity of antibiotics in combination. In: Bondi A, Bartola IT, Prier JE, editors. The clinical laboratory as an aid in chemotherapy of infectious diseases. Baltimore: University Park Press; 1977.

  13. Lorian V. Antimicrobial combinations, chapter 9, in Antibiotics in Laboratory Medicine, p. 365–441, Lippincott Williams and Wilkins, Philadelphia, 2005.

  14. Bonapace CA, Bosso JA, Friedrich LV, White RL. Comparison of methods of interpretation of checkerboard synergy testing. Diag Micro Infect Dis. 2002;44:363–6.

    Article  Google Scholar 

  15. Elion GB, Singer S. Hitchings GH Antagonism of nucleic acid derivatives. J Biol Chem. 1954;208:477–88.

    Article  CAS  PubMed  Google Scholar 

  16. Doern CD. When does 2 plus 2 equal 5? A review of antimicrobial synergy testing. J Clin Microbiol. 2014;52:4124–8.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Stevens DA, Vo PT. Synergistic interaction of trimethoprim and sulfamethoxazole on Paracoccidioides brasiliensis. Antimicrob Agents Chemother. 1982;21:852–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Denning DW, Hanson LH, Perlman AM, Stevens DA. In vitro susceptibility and synergy studies of Aspergillus species to conventional and new agents. Diagn Microbiol Infect Dis. 1992;15:21–34. https://doi.org/10.1016/0732-8893(92)90053-v. (PMID: 1309690).

    Article  CAS  PubMed  Google Scholar 

  19. Stevens DA. Drug interaction studies of a glucan synthase inhibitor (LY 303366) and a chitin synthase inhibitor (Nikkomycin Z) for inhibition and killing of fungal pathogens. Antimicrob Agents Chemother. 2000;44:2547–8. https://doi.org/10.1128/AAC.44.9.2547-2548.2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hoeprich PD, Finn PD. Obfuscation of the activity of antifungal antimicrobics by culture media. J Infect Dis. 1972;126:353–61.

    Article  CAS  PubMed  Google Scholar 

  21. The European Committee on Antimicrobial Susceptibility Testing, version 10.0, 2020.http://www.eucast.org/astoffungi/clinicalbreakpointsforantifungals/

  22. Catz P, Green CE. Analysis of mouse plasma, brain and lung samples for nikkomycin Z. SRI International, Menlo Park, CA, 2020.

  23. Mihalcea E, Licollari AA. Single oral dose range finding study followed by a 7-day repeated dose and pharmacokinetic study of NikZ in mice. Nucro-Technics Study no. 346295. Nucro-Technics, Scarborough, Ontario, Canada, 2019.

  24. Mirdamadi K, Licollari A, Tan A. Evaluation of plasma concentrations of nikkomycin following administration to mice in drinking water. Nucro-Technics Study no. 374222. Nucro-Technics, Scarborough, Ontario, Canada, 2021.

  25. Nix DE, Swezey RR, Hector R, Galgiani JN. Pharmacokinetics of nikkomycin Z after single rising oral doses. Antimicrob Agents Chemother. 2009;53:2517–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Clemons KV, Stevens DA. Efficacy of nikkomycin Z against experimental pulmonary blastomycosis. Antimicrob Agents Chemother. 1997;41:2026–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sass G, Larwood DJ, Martinez M, Chatterjee P, Xavier MO, Stevens DA. Nikkomycin Z against disseminated coccidioidomycosis in a murine model of sustained release dosing. Antimicrob Agents Chemother. 2021;65: e0028521.

    Article  PubMed  Google Scholar 

  28. Larwood DJ. Nikkomycin Z-ready to meet the promise? J Fungi (Basel). 2020;6:261.

    Article  CAS  PubMed  Google Scholar 

  29. Hector RF, Zimmer BL, Pappagianis D. Evaluation of nikkomycins X and Z in murine models of coccidioidomycosis, histoplasmosis and blastomycosis. Antimicrob Agents Chemother. 1990;34:587–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cheung YY, Hul M. Effects of echinocandins in combination with nikkomycin Z against invasive Candida albicans bloodstream isolates and the fks mutants. Antimicrob Agents Chemother. 2017;61:e00619-e717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kovacs R, Nagy F, Toth Z, Bozo A, Balasz B, Majoros L. Synergistic effects of nikkomycin Z with caspofungin and micafungin against Candida albicans and Candida parapsilosis biofilms. Lett Appl Microbiol. 2019;69:271–8.

    Article  CAS  PubMed  Google Scholar 

  32. Becker JM, Marcus S, Tullock J, Miller D, Krainer E, Khare RK, Naider F. Use of the chitin-synthesis inhibitor nikkomycin to treat disseminated candidiasis in mice. J Infect Dis. 1988;157:212–4.

    Article  CAS  PubMed  Google Scholar 

  33. Chapman T, Kinsman O, Houston J. Chitin biosynthesis in Candida albicans grown in vitro and in vivo and its inhibition by nikkomycin Z. Antimicrob Agents Chemother. 1992;36:1909–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Braun P, Calderone RA. Chitin synthesis in Candida albicans: comparison of yeast and hyphal forms. J Bact. 1978;135:1472–7.

    Article  Google Scholar 

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Acknowledgements

The authors thank Marife Martinez for excellent technical support. This work was supported by the Foundation for Research in Infectious Diseases (FRID, Grant 8201), and from the David and Mary Larwood Family Charitable Fund. The funders had no input into the study design or interpretation of the results.

Author information

Authors and Affiliations

  1. California Institute for Medical Research, San Jose, CA, USA

    Gabriele Sass, David J. Larwood & David A. Stevens

  2. Valley Fever Solutions, Tucson, AZ, USA

    David J. Larwood

  3. Division of Infectious Diseases and Geographic Medicine, Stanford University Medical School, Stanford, CA, USA

    David A. Stevens

Authors
  1. Gabriele Sass
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  2. David J. Larwood
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  3. David A. Stevens
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by GS, DJL, and DAS. The first draft of the manuscript was written by DAS and all authors contributed to subsequent versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Gabriele Sass.

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Conflict of interest

Valley Fever Solutions promotes the development of NZ for therapy of coccidioidomycosis. D. J. Larwood is a principal in Valley Fever Solutions. The other authors have no relevant financial or non-financial interests to disclose.

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Sass, G., Larwood, D.J. & Stevens, D.A. Synergy In Vitro of Nikkomycin Z with Azole Against the Invasive Form of Candida albicans. Mycopathologia 188, 949–956 (2023). https://doi.org/10.1007/s11046-023-00788-0

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