High-Throughput Screening of the Repurposing Hub Library to Identify Drugs with Novel Inhibitory Activity against Candida albicans and Candida auris Biofilms.
High-Throughput Screening of the Repurposing Hub Library to Identify Drugs with Novel Inhibitory Activity against Candida albicans and Candida auris Biofilms.
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DOI：
10.3390/jof9090879
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发表时间：
2023-08-27
期刊：
影响因子：
--
通讯作者：
Lopez-Ribot JL
中科院分区：
文献类型：
--
作者：
Ajetunmobi OH;Wall G;Vidal Bonifacio B;Martinez Delgado LA;Chaturvedi AK;Najvar LK;Wormley FL Jr;Patterson HP;Wiederhold NP;Patterson TF;Lopez-Ribot JL
念珠菌病是最常见的医院感染之一，影响越来越多的高危患者。白色念珠菌仍然是念珠菌病最常见的病原体，但是，在过去的十年中，C。耳炎已经成为一种强大的多重抗药性病原体。这两个物种都完全能够形成生物膜，这有助于耐药性，增加了新的有效抗真菌治疗的紧迫性。改变现有药物的用途可以显著加速抗念珠菌病新疗法的开发。在这里，我们筛选了来自布罗德研究所的Repurposing Hub库，其中包含6000多种化合物，以寻找C的抑制剂。白色念珠菌和C.耳生物膜形成。初步筛选鉴定出57个针对C的初始命中。白色念珠菌33株，白色念珠菌33株。耳。使用炎性浓度依赖性测定来验证初始命中的活性，并同时建立其抗生物膜效力。基于这些结果，依布硒啉、替西罗莫司和化合物BAY 11-7082成为主要的可重新定位化合物。随后的实验确定了它们对酵母和丝状真菌的抗真菌活性谱。此外，在小鼠造血播散性念珠菌模型中检测了它们的体内活性。白色念珠菌和C.耳感染。尽管前景光明，但还需要进一步的体外和体内研究来确认它们在治疗念珠菌病和可能的其他真菌感染方面的潜在用途。
Candidiasis is one of the most frequent nosocomial infections affecting an increasing number of at-risk patients. Candida albicans remains the most frequent causative agent of candidiasis, but, in the last decade, C. auris has emerged as a formidable multi-drug-resistant pathogen. Both species are fully capable of forming biofilms, which contribute to resistance, increasing the urgency for new effective antifungal therapies. Repurposing existing drugs could significantly accelerate the development of novel therapies against candidiasis. Here, we have screened the Repurposing Hub library from the Broad Institute, containing over 6000 compounds, in search for inhibitors of C. albicans and C. auris biofilm formation. The primary screen identified 57 initial hits against C. albicans and 33 against C. auris. Confirmatory concentration-dependent assays were used to validate the activity of the initial hits and, at the same time, establish their anti-biofilm potency. Based on these results, ebselen, temsirolimus, and compound BAY 11-7082 emerged as the leading repositionable compounds. Subsequent experiments established their spectrum of antifungal activity against yeasts and filamentous fungi. In addition, their in vivo activity was examined in the murine models of hematogenously disseminated C. albicans and C. auris infections. Although promising, further in vitro and in vivo studies are needed to confirm their potential use for the therapy of candidiasis and possibly other fungal infections.
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DOI：
10.1007/978-1-0716-3155-3_5
发表时间：
2023-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Ajetunmobi, Olabayo H;Wall, Gina;Lopez-Ribot, Jose L
通讯作者：
Lopez-Ribot, Jose L
影响因子：
24.5
作者：
Dotan, Iris;Rachmilewitz, Daniel;Hommes, Daniel
通讯作者：
Hommes, Daniel
影响因子：
2.8
作者：
Azad, Gajendra Kumar;Tomar, Raghuvir S.
通讯作者：
Tomar, Raghuvir S.
影响因子：
23.9
作者：
Ben-David, Uri;Gan, Qing-Fen;Benvenisty, Nissim
通讯作者：
Benvenisty, Nissim
影响因子：
4.6
作者：
Lee J;Rhee MH;Kim E;Cho JY
通讯作者：
Cho JY