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利用高通量药物再利用筛选技术鉴定抗多药耐药性耳念珠菌的抗真菌化合物。

Identification of Antifungal Compounds against Multidrug-Resistant Candida auris Utilizing a High-Throughput Drug-Repurposing Screen.

机构信息

National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

出版信息

Antimicrob Agents Chemother. 2021 Mar 18;65(4). doi: 10.1128/AAC.01305-20.

Abstract

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 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- 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 .

摘要

是一种新兴的致命真菌感染,已在医院和护理机构引发了多次疫情。目前的治疗选择受到耐药性发展的限制。因此,需要发现新的药物来对抗这些耐药性感染,以满足这一未满足的医疗需求。我们已经建立了一种基于生物发光 ATP 的测定法,以鉴定新的化合物和潜在的药物组合,这些化合物和潜在的药物组合对多种多药耐药的菌株表现出有效的生长抑制作用。该测定法稳健且适用于通过高通量筛选 (HTS) 评估大型化合物库。利用该测定法,我们对 4314 种已批准的药物和具有药理活性的化合物进行了筛选,得到了 25 种化合物,其中包括 6 种新型抗真菌化合物和 13 组潜在的二联药物组合。在药物组合中,丝氨酸棕榈酰转移酶抑制剂米卡芬净在筛选过程中与氟胞嘧啶联合显示出对所有测试分离株的组合效果。在 13 株临床分离株中证实了这种组合效应。

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