1887

Abstract

In this study, we demonstrated that in distilled water, a nutrient-starved condition that elicits autophagy in , an array of autophagy-deficient mutants are resistant to the fungicidal effects of amphotericin B. In addition, we found that a dansyl-labelled derivative of the antibiotic colocalized with disintegrated vacuoles throughout the cytoplasm in the amphotericin B-sensitive parental strain suspended in distilled water. In contrast, the dansyl-labelled derivative was not internalized in the Δ strain, which is deficient in the formation of autophagosomes, a key early step in autophagy. However, the derivative accumulated without significant toxicity in structurally intact vacuoles in the Δ mutant, which is deficient in the degradation of autophagic bodies, the final stage in autophagy. Our data support the idea that amphotericin B can utilize autophagy-dependent trafficking into the intra-vacuolar lumen, where it interacts with the luminal leaf of the membrane to cause structurally catastrophic effects.

Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.000269
2016-05-01
2024-12-09
Loading full text...

Full text loading...

/deliver/fulltext/micro/162/5/848.html?itemId=/content/journal/micro/10.1099/mic.0.000269&mimeType=html&fmt=ahah

References

  1. Anderson T. M., Clay M. C., Cioffi A. G., Diaz K. A., Hisao G. S., Tuttle M. D., Nieuwkoop A. J., Comellas G., Maryum N., other authors. 2014; Amphotericin forms an extramembranous and fungicidal sterol sponge. Nat Chem Biol 10:400–406 [View Article][PubMed]
    [Google Scholar]
  2. Baginski M., Sternal K., Czub J., Borowski E. 2005; Molecular modelling of membrane activity of amphotericin B, a polyene macrolide antifungal antibiotic. Acta Biochim Pol 52:655–658[PubMed]
    [Google Scholar]
  3. Borjihan H., Ogita A., Fujita K., Hirasawa E., Tanaka T. 2009; The vacuole-targeting fungicidal activity of amphotericin B against the pathogenic fungus Candida albicans and its enhancement by allicin. J Antibiot (Tokyo) 62:691–697 [View Article][PubMed]
    [Google Scholar]
  4. Carrillo-Muñoz A. J., Giusiano G., Ezkurra P. A., Quindós G. 2006; Antifungal agents: mode of action in yeast cells. Rev Esp Quimioter 19:130–139[PubMed]
    [Google Scholar]
  5. Chen W. C., Chou D. L., Feingold D. S. 1978; Dissociation between ion permeability and the lethal action of polyene antibiotics on Candida albicans . Antimicrob Agents Chemother 13:914–917 [View Article][PubMed]
    [Google Scholar]
  6. Kang C. K., Yamada K., Usuki Y., Ogita A., Fujita K., Tanaka T. 2013; Visualization analysis of the vacuole-targeting fungicidal activity of amphotericin B against the parent strain and an ergosterol-less mutant of Saccharomyces cerevisiae . Microbiology 159:939–947 [View Article][PubMed]
    [Google Scholar]
  7. Kato M., Wickner W. 2001; Ergosterol is required for the Sec18/ATP-dependent priming step of homotypic vacuole fusion. EMBO J 20:4035–4040 [View Article][PubMed]
    [Google Scholar]
  8. Kim J. H., Faria N. C., Martins MdeL., Chan K. L., Campbell B. C. 2012; Enhancement of antimycotic activity of amphotericin B by targeting the oxidative stress response of Candida and cryptococcus with natural dihydroxybenzaldehydes. Front Microbiol 3:261[PubMed]
    [Google Scholar]
  9. Martel C. M., Parker J. E., Bader O., Weig M., Gross U., Warrilow A. G., Kelly D. E., Kelly S. L. 2010; A clinical isolate of Candida albicans with mutations in ERG11 (encoding sterol 14alpha-demethylase) and ERG5 (encoding C22 desaturase) is cross resistant to azoles and amphotericin B. Antimicrob Agents Chemother 54:3578–3583 [View Article][PubMed]
    [Google Scholar]
  10. Nakamura N., Matsuura A., Wada Y., Ohsumi Y. 1997; Acidification of vacuoles is required for autophagic degradation in the yeast, Saccharomyces cerevisiae . J Biochem 121:338–344 [View Article][PubMed]
    [Google Scholar]
  11. Nakatogawa H., Suzuki K., Kamada Y., Ohsumi Y. 2009; Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 10:458–467 [View Article][PubMed]
    [Google Scholar]
  12. Nakayama K., Yamaguchi T., Doi T., Usuki Y., Taniguchi M., Tanaka T. 2002; Synergistic combination of direct plasma membrane damage and oxidative stress as a cause of antifungal activity of polyol macrolide antibiotic niphimycin. J Biosci Bioeng 94:207–211 [View Article][PubMed]
    [Google Scholar]
  13. Obara K., Sekito T., Niimi K., Ohsumi Y. 2008; The Atg18-Atg2 complex is recruited to autophagic membranes via phosphatidylinositol 3-phosphate and exerts an essential function. J Biol Chem 283:23972–23980 [View Article][PubMed]
    [Google Scholar]
  14. Ogita A., Fujita K., Taniguchi M., Tanaka T. 2006; Enhancement of the fungicidal activity of amphotericin B by allicin, an allyl-sulfur compound from garlic, against the yeast Saccharomyces cerevisiae as a model system. Planta Med 72:1247–1250 [View Article][PubMed]
    [Google Scholar]
  15. Ogita A., Matsumoto K., Fujita K., Usuki Y., Hatanaka Y., Tanaka T. 2007; Synergistic fungicidal activities of amphotericin B and N-methyl-N ″-dodecylguanidine: a constituent of polyol macrolide antibiotic niphimycin. J Antibiot (Tokyo) 60:27–35 [View Article][PubMed]
    [Google Scholar]
  16. Ogita A., Yutani M., Fujita K., Tanaka T. 2010; Dependence of vacuole disruption and independence of potassium ion efflux in fungicidal activity induced by combination of amphotericin B and allicin against Saccharomyces cerevisiae . J Antibiot (Tokyo) 63:689–692[PubMed]
    [Google Scholar]
  17. Ogita A., Fujita K., Tanaka T. 2012; Enhancing effects on vacuole-targeting fungicidal activity of amphotericin B. Front Microbiol 3:100[PubMed] [CrossRef]
    [Google Scholar]
  18. Pichler H., Riezman H. 2004; Where sterols are required for endocytosis. Biochim Biophys Acta 1666:51–61 [View Article][PubMed]
    [Google Scholar]
  19. Pinjon E., Moran G. P., Jackson C. J., Kelly S. L., Sanglard D., Coleman D. C., Sullivan D. J. 2003; Molecular mechanisms of itraconazole resistance in Candida dubliniensis . Antimicrob Agents Chemother 47:2424–2437 [View Article][PubMed]
    [Google Scholar]
  20. Ramotowski S., Szcześniak M. 1967; [Determination of potassium salt content in pharmaceutical preparations by means of sodium tetraphenylborate]. Acta Pol Pharm 24:605–613 (in Polish)[PubMed]
    [Google Scholar]
  21. Reggiori F., Klionsky D. J. 2013; Autophagic processes in yeast: mechanism, machinery and regulation. Genetics 194:341–361 [View Article][PubMed]
    [Google Scholar]
  22. Takeshige K., Baba M., Tsuboi S., Noda T., Ohsumi Y. 1992; Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J Cell Biol 119:301–311 [View Article][PubMed]
    [Google Scholar]
  23. Vida T. A., Emr S. D. 1995; A new vital stain for visualizing vacuolar membrane dynamics and endocytosis in yeast. J Cell Biol 128:779–792 [View Article][PubMed]
    [Google Scholar]
  24. Yang Z., Klionsky D. J. 2010; Eaten alive: a history of macroautophagy. Nat Cell Biol 12:814–822 [View Article][PubMed]
    [Google Scholar]
  25. Young L. Y., Hull C. M., Heitman J. 2003; Disruption of ergosterol biosynthesis confers resistance to amphotericin B in Candida lusitaniae . Antimicrob Agents Chemother 47:2717–2724 [View Article][PubMed]
    [Google Scholar]
  26. Yutani M., Ogita A., Usuki Y., Fujita K., Tanaka T. 2011; Enhancement effect of N-methyl-N″-dodecylguanidine on the vacuole-targeting fungicidal activity of amphotericin B against the pathogenic fungus Candida albicans . J Antibiot (Tokyo) 64:469–474 [View Article][PubMed]
    [Google Scholar]
/content/journal/micro/10.1099/mic.0.000269
Loading
/content/journal/micro/10.1099/mic.0.000269
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error