Induction of amphotericin B resistance in susceptible Candida auris by extracellular vesicles

ABSTRACT

Drug resistance derived from extracellular vesicles (EVs) is an increasingly important research area but has seldom been described regarding fungal pathogens. Here, we characterized EVs derived from a triazole-resistant but amphotericin B-susceptible strain of Candida auris. Nano- to microgram concentrations of C. auris EVs prepared from both broth and solid agar cultures could robustly increase the yeast’s survival against both pure and clinical amphotericin B formulations in a dose-dependent manner, resulting in up to 16-fold changes of minimum inhibitory concentration. Meanwhile, this effect was not observed upon addition of these EVs to C. albicans, nor upon addition of C. albicans EVs to C. auris. No change in susceptibilities was observed upon EV treatment for fluconazole, voriconazole, micafungin, and flucytosine. Mass spectrometry indicated the presence of immunogenic-/drug resistance-implicated proteins in C. auris EVs, including alcohol dehydrogenase 1 as well as C. albicans Mp65-like and Xog1-like proteins in high quantities. Based on these observations, we propose a potential species-specific role for EVs in amphotericin B resistance in C. auris. These observations may provide critical insights into treatment of multidrug-resistant C. auris.

KEYWORDS:

• Candida auris
• extracellular vesicles
• drug resistance
• amphotericin B
• solid media EV purification

Acknowledgements

We thank the Department of Pathology, HKU for the use of their nanoparticle tracking analysis machine and technical expertise; the Electron Microscope Unit, HKU for their technical support and assistance in sample preparation for TEM; and the Proteomics and Metabolomics Unit, HKU for their technical support and assistance in performing LC–MS.

Disclosure statement

Patrick Chiu-Yat Woo has provided scientific advisory/laboratory services for Gilead Sciences, Incorporated; International Health Management Associates, Incorporated; Merck & Corporation, Incorporated; Micología Molecular S.L. and Pfizer, Incorporated. The other authors report no conflict of interest. The funding sources had no role in study design, data collection, analysis, interpretation, or writing of the report. The authors alone are responsible for the content and the writing of the manuscript.

Ethics statement

The use of clinical C. auris isolate in this study and leftover human blood specimens was approved by the Institutional Review Board of The University of Hong Kong/Hospital Authority Hong Kong West Cluster (UW 16-365).

Additional information

Funding

This work was partly supported by the General Research Fund, Research Grants Council, University Grants Committee; as well as the framework of the Higher Education Sprout Project by the Ministry of Education (MOE-111-S-023-A) in Taiwan.