期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 65, 期 4, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01305-20
关键词
Candida auris; drug repurposing; drug combination therapy; multidrug resistance
资金
- Intramural Research Program of National Center for Advancing Translational Sciences, National Institutes of Health (NIH)
- National Institutes of Allergy and Infectious Diseases, National Institutes of Health (NIH)
- NIH [AI136934, AI125770]
- Veterans Affairs Program [I01BX002924]
A bioluminescent ATP-based assay was established to identify new compounds and potential drug combinations effective against drug-resistant Candida auris. Screenings of approved drugs and pharmacologically active compounds yielded 25 compounds, including novel anti-Candida auris compounds and potential two-drug combinations that showed promising effects in vitro and in clinical isolates.
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 awls 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.
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