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Published on: February 14, 2018
Identification of Antifungal Compounds against Multidrug-Resistant Candida auris Utilizing a High-Throughput
Yu-Shan Cheng1, Jose Santinni Roma2, Min Shen1
1National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
Abstract:
Candida auris is an emerging fatal fungal infection that has resulted in several outbreaks in hospitals and care facilities. Current treatment options are limited by the development of drug resistance. Identification of new pharmaceuticals to combat these drug-resistant infections will thus be required to overcome this unmet medical need. We have established a bioluminescent ATP-based assay to identify new compounds and potential drug combinations showing effective growth inhibition against multiple strains of multidrug-resistant Candida auris The assay is robust and suitable for assessing large compound collections by high-throughput screening (HTS). Utilizing this assay, we conducted a screen of 4,314 approved drugs and pharmacologically active compounds that yielded 25 compounds, including 6 novel anti-Candida auris compounds and 13 sets of potential two-drug combinations. Among the drug combinations, the serine palmitoyltransferase inhibitor myriocin demonstrated a combinational effect with flucytosine against all tested isolates during screening. This combinational effect was confirmed in 13 clinical isolates of Candida auris.
Insights
Researchers screened 4,314 drugs to find new treatments for multidrug-resistant Candida auris infections. A combination of myriocin and flucytosine showed promising results against this fatal fungal pathogen.
Area of Science:
- Medical Mycology
- Infectious Diseases
- Drug Discovery
Background:
- Emerging threat of multidrug-resistant *Candida auris* fungal infections.
- Limited current treatment options due to rapid drug resistance development.
- Urgent need for novel therapeutic strategies against *Candida auris*.
Purpose of the Study:
- To establish and utilize a high-throughput screening (HTS) assay for identifying new anti-*Candida auris* compounds.
- To discover effective drug combinations against multidrug-resistant *Candida auris* strains.
- To address the unmet medical need for novel treatments against fatal fungal infections.
Main Methods:
- Development of a bioluminescent ATP-based assay for growth inhibition.
- High-throughput screening of 4,314 approved drugs and pharmacologically active compounds.
- Validation of identified compounds and drug combinations against clinical isolates of *Candida auris*.
Main Results:
- Screening identified 25 compounds, including 6 novel anti-*Candida auris* agents.
- Discovered 13 potential two-drug combinations effective against *Candida auris*.
- Myriocin and flucytosine combination demonstrated significant growth inhibition against all tested isolates.
Conclusions:
- The developed HTS assay is robust for identifying anti-*Candida auris* therapeutics.
- The myriocin-flucytosine combination shows potential as a new treatment strategy.
- Further research into drug combinations is crucial for combating drug-resistant *Candida auris* infections.
