BACKGROUND Invasive aspergillosis is a fungal infection that occurs mainly in immunocompromised patients. It is responsible for a high degree of mortality and is invariably unresponsive to conventional antifungal treatments. Histone deacetylase inhibitors can affect the cell cycle, apoptosis and differentiation. The histone deacetylase inhibitor vorinostat (SAHA) has recently received approval for the treatment of cutaneous T cell lymphoma. Here, we investigated the interactions of SAHA and itraconazole, voriconazole, and posaconazole against Aspergillus spp. in vitro using both planktonic cells and biofilms. RESULTS We investigated 20 clinical strains using broth microdilution checkerboard methods. The results showed synergy between SAHA and itraconazole, voriconazole, and posaconazole against 60, 40, and 25% of tested isolates of planktonic Aspergillus spp., respectively. Similar synergy was also observed against Aspergillus biofilms. The expression of the azole-associated multidrug efflux pumps MDR1, MDR2, MDR3 and MDR4, as well as that of HSP90, was measured by RT-PCR. The results indicated that the molecular mechanism of the observed synergistic effects in Aspergillus fumigatus may be partly associated with dampened expression of the efflux pump genes and, furthermore, that HSP90 suppression may be a major contributor to the observed synergistic effects of the drugs. CONCLUSIONS SAHA has potential as a secondary treatment to enhance the effects of azoles against both biofilm and planktonic cells of Aspergillus spp. in vitro. This effect occurs mostly by inhibition of HSP90 expression.

中文翻译：

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伏立诺他 (SAHA) 和唑类对曲霉属及其生物膜的协同作用。


背景技术侵袭性曲霉病是一种真菌感染，主要发生在免疫功能低下的患者中。它造成很高的死亡率，并且对传统的抗真菌治疗总是没有反应。组蛋白脱乙酰酶抑制剂可以影响细胞周期、细胞凋亡和分化。组蛋白脱乙酰酶抑制剂伏立诺他（SAHA）最近获得批准用于治疗皮肤 T 细胞淋巴瘤。在这里，我们研究了 SAHA 与伊曲康唑、伏立康​​唑和泊沙康唑对抗曲霉属的相互作用。在体外使用浮游细胞和生物膜。结果 我们使用肉汤微量稀释棋盘法研究了 20 种临床菌株。结果显示，SAHA 与伊曲康唑、伏立康​​唑和泊沙康唑之间分别对 60%、40% 和 25% 的浮游曲霉属测试菌株有协同作用。针对曲霉菌生物膜也观察到类似的协同作用。通过 RT-PCR 测量唑相关多药外排泵 MDR1、MDR2、MDR3 和 MDR4 以及 HSP90 的表达。结果表明，在烟曲霉中观察到的协同效应的分子机制可能部分与外排泵基因的表达减弱有关，此外，HSP90 抑制可能是观察到的药物协同效应的主要贡献者。结论 SAHA 具有作为辅助治疗的潜力，可增强唑类对曲霉属生物膜和浮游细胞的作用。体外。这种效应主要是通过抑制 HSP90 表达而发生的。