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Concise CommunicationIn-Press PreviewInfectious diseaseTherapeutics Free access | 10.1172/JCI145123

Turbinmicin inhibits Candida biofilm growth by disrupting fungal vesicle-mediated trafficking

Miao Zhao,1 Fan Zhang,2 Robert Zarnowski,1 Kenneth J. Barns,2 Ryley Jones,1 Jen L. Fossen,1 Hiram Sanchez,1 Scott R. Rajski,2 Anjon Audhya,3 Tim S. Bugni,2 and David R. Andes1

1Department of Medicine, University of Wisconsin, Madison, United States of America

2Pharmaceutical Sciences Division, University of Wisconsin, Madison, United States of America

3Department of Biomolecular Chemistry, University of Wisconsin, Madison, United States of America

Find articles by Zhao, M. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Wisconsin, Madison, United States of America

2Pharmaceutical Sciences Division, University of Wisconsin, Madison, United States of America

3Department of Biomolecular Chemistry, University of Wisconsin, Madison, United States of America

Find articles by Zhang, F. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Wisconsin, Madison, United States of America

2Pharmaceutical Sciences Division, University of Wisconsin, Madison, United States of America

3Department of Biomolecular Chemistry, University of Wisconsin, Madison, United States of America

Find articles by Zarnowski, R. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Wisconsin, Madison, United States of America

2Pharmaceutical Sciences Division, University of Wisconsin, Madison, United States of America

3Department of Biomolecular Chemistry, University of Wisconsin, Madison, United States of America

Find articles by Barns, K. in: JCI | PubMed | Google Scholar

1Department of Medicine, University of Wisconsin, Madison, United States of America

2Pharmaceutical Sciences Division, University of Wisconsin, Madison, United States of America

3Department of Biomolecular Chemistry, University of Wisconsin, Madison, United States of America

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1Department of Medicine, University of Wisconsin, Madison, United States of America

2Pharmaceutical Sciences Division, University of Wisconsin, Madison, United States of America

3Department of Biomolecular Chemistry, University of Wisconsin, Madison, United States of America

Find articles by Fossen, J. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Wisconsin, Madison, United States of America

2Pharmaceutical Sciences Division, University of Wisconsin, Madison, United States of America

3Department of Biomolecular Chemistry, University of Wisconsin, Madison, United States of America

Find articles by Sanchez, H. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Wisconsin, Madison, United States of America

2Pharmaceutical Sciences Division, University of Wisconsin, Madison, United States of America

3Department of Biomolecular Chemistry, University of Wisconsin, Madison, United States of America

Find articles by Rajski, S. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Wisconsin, Madison, United States of America

2Pharmaceutical Sciences Division, University of Wisconsin, Madison, United States of America

3Department of Biomolecular Chemistry, University of Wisconsin, Madison, United States of America

Find articles by Audhya, A. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Wisconsin, Madison, United States of America

2Pharmaceutical Sciences Division, University of Wisconsin, Madison, United States of America

3Department of Biomolecular Chemistry, University of Wisconsin, Madison, United States of America

Find articles by Bugni, T. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Wisconsin, Madison, United States of America

2Pharmaceutical Sciences Division, University of Wisconsin, Madison, United States of America

3Department of Biomolecular Chemistry, University of Wisconsin, Madison, United States of America

Find articles by Andes, D. in: JCI | PubMed | Google Scholar

Published December 29, 2020 - More info

J Clin Invest. https://doi.org/10.1172/JCI145123.
Copyright © 2020, American Society for Clinical Investigation
Published December 29, 2020 - Version history
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Abstract

The emergence of drug-resistant fungi has prompted an urgent threat alert from the Centers for Disease Control. Biofilm assembly by these pathogens further impairs effective therapy. We recently identifed an antifungal, turbinmicin, that inhibits the fungal vesicle-mediated trafficking pathway and demonstrates broad-spectrum activity against planktonically growing fungi. During biofilm growth, vesicles with unique features play a critical role in the delivery of the biofilm extracellular matrix components. As these components are largely responsible for the drug resistance associated with biofilm growth, we explored the utility of turbinmicin in the biofilm setting. We found that turbinmicin disrupts extracellular vesicle delivery during biofilm growth, and this impairs the subsequent assembly of the biofilm matrix. We demonstrated that elimination of the extracellular matrix renders the drug-resistant biofilm communities susceptible to fungal killing by turbinmicin. Furthermore, the addition of turbinmicin to otherwise ineffective antifungal therapy potentiated the activity of these drugs. The underlying role of vesicles explains this dramatic activity and was supported by phenotype reversal with the addition of exogenous biofilm extracellular vesicles. This striking capacity to cripple biofilm assembly mechanisms reveals a new approach to eradicating biofilms and sheds light on turbinmicin as a promising anti-biofilm drug.

Supplemental material

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Version history
  • Version 1 (December 29, 2020): In-Press Preview
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