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Aprepitant, an antiemetic agent, interferes with metal ion homeostasis of Candida auris and displays potent synergistic interactions with azole drugs
Virulence ( IF 5.2 ) Pub Date : 2020-10-26 , DOI: 10.1080/21505594.2020.1838741
Hassan E Eldesouky 1, 2 , Nadia A Lanman 1, 3 , Tony R Hazbun 4 , Mohamed N Seleem 1, 2
Affiliation  

ABSTRACT

With the rapid increase in the frequency of azole-resistant species, combination therapy appears to be a promising tool to augment the antifungal activity of azole drugs against resistant Candida species. Here, we report the effect of aprepitant, an antiemetic agent, on the antifungal activities of azole drugs against the multidrug-resistant Candida auris. Aprepitant reduced the minimum inhibitory concentration (MIC) of itraconazole in vitro, by up to eight-folds. Additionally, the aprepitant/itraconazole combination interfered significantly with the biofilm-forming ability of C. auris by 95 ± 0.13%, and significantly disrupted mature biofilms by 52 ± 0.83%, relative to the untreated control. In a Caenorhabditis elegans infection model, the aprepitant/itraconazole combination significantly prolonged the survival of infected nematodes by ~90% (five days post-infection) and reduced the fungal burden by ~92% relative to the untreated control. Further, this novel drug combination displayed broad-spectrum synergistic interactions against other medically important Candida species such as C. albicans, C. krusei, C. tropicalis, and C. parapsilosis (ƩFICI ranged from 0.08 to 0.31). Comparative transcriptomic profiling and mechanistic studies indicated aprepitant/itraconazole interferes significantly with metal ion homeostasis and compromises the ROS detoxification ability of C. auris. This study presents aprepitant as a novel, potent, and broad-spectrum azole chemosensitizing agent that warrants further investigation.



中文翻译:

Aprepitant是一种止吐药,可干扰金葡菌的金属离子稳态,并显示出与唑类药物的有效协同作用

摘要

随着对唑类药物耐药性种类的频率迅速增加,联合治疗似乎是增加唑类药物对耐药性念珠菌种类的抗真菌活性的有前途的工具。在这里,我们报告了止吐剂阿瑞吡坦对唑类药物对耐多药假丝酵母的抗真菌活性的影响。阿瑞匹坦在体外将伊曲康唑的最低抑菌浓度(MIC)降低了八倍。此外,该阿瑞吡坦/伊曲康唑组合显著与生物膜形成能力干扰C.耳由95±0.13%,和显著破坏成熟由52±0.83%的生物膜,相对于未处理的对照。在秀丽隐杆线虫中与未治疗的对照组相比,阿瑞匹坦/伊曲康唑的组合可将感染的线虫的存活时间延长约90%(感染后五天),并将真菌负担减少约92%。此外,这种新颖的药物组合显示对其他医学上重要的广谱的协同相互作用念珠菌物种如白色念珠菌,克柔念珠菌,热带念珠菌近平滑念珠菌(ΣFICI范围从0.08至0.31)。对比转录组分析和机理研究表明,aprepitant /伊曲康唑显着干扰金属离子的稳态,并损害金龟子的ROS解毒能力。这项研究提出了一种新的,有效的,广谱的吡唑化学增敏剂,值得进一步研究。

更新日期:2020-10-30
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