Department of Otorhinolaryngology and Head Neck Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, 510630, Guangdong, People's Republic of China.
Department of Otolaryngology Head Neck Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, People's Republic of China.
BMC Microbiol. 2020 Feb 7;20(1):28. doi: 10.1186/s12866-020-1718-x.
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.
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.
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.
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。它导致高度的死亡率，并且对常规抗真菌治疗始终没有反应。组蛋白去乙酰化酶抑制剂可以影响细胞周期、凋亡和分化。组蛋白去乙酰化酶抑制剂伏立诺他（SAHA）最近已被批准用于治疗皮肤 T 细胞淋巴瘤。在这里，我们使用浮游细胞和生物膜研究了 SAHA 与伊曲康唑、伏立康唑和泊沙康唑之间的相互作用，以对抗体外的曲霉菌属。
我们使用肉汤微量稀释棋盘法研究了 20 株临床分离株。结果表明，SAHA 与伊曲康唑、伏立康唑和泊沙康唑对浮游曲霉菌属的 60%、40%和 25%的测试分离株具有协同作用。在对抗曲霉生物膜时也观察到类似的协同作用。通过 RT-PCR 测量唑类相关多药外排泵 MDR1、MDR2、MDR3 和 MDR4 以及 HSP90 的表达。结果表明，观察到的烟曲霉协同作用的分子机制可能部分与外排泵基因表达减弱有关，此外，HSP90 抑制可能是观察到药物协同作用的主要原因。
SAHA 具有作为辅助治疗的潜力，可增强唑类药物对曲霉属生物膜和浮游细胞的体外作用。这种作用主要通过抑制 HSP90 表达来实现。
