Department of Pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, People's Republic of China.
Department of Pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, People's Republic of China.
J Glob Antimicrob Resist. 2021 Mar;24:296-302. doi: 10.1016/j.jgar.2020.10.025. Epub 2021 Jan 26.
Candida albicans is a yeast that causes fungal infections with high mortality and is typically resistant to azole drugs. To overcome this resistance, we explored the combined use of oridonin (ORI) and three azole drugs, namely fluconazole (FLC), itraconazole (ITR) and voriconazole (VOR). Azole-resistant C. albicans strains were obtained from cancer patients and the reversal of drug resistance in these strains was investigated.
The synergistic antifungal activity of ORI and azole drugs was measured by checkerboard microdilution and time-kill assays. The resistance reversal mechanisms, namely inhibition of drug efflux and induction of apoptosis, were investigated by flow cytometry. Expression levels of the efflux pump-related genesCDR1 and CDR2 were assessed by RT-qPCR.
The efflux pump inhibition assay with ORI showed that the minimum inhibitory concentrations (MICs) of FLC (128-fold), ITR (64-fold) and VOR (250-fold) decreased significantly. Upregulation of genes encodingCDR1 and CDR2 was confirmed in the resistant strain. The sensitising effect of ORI on FLC in the treatment of C. albicans also included the promotion of apoptosis.
We demonstrated that combining azoles with ORI exerted potent synergism and that ORI could promote sensitisation to azoles in azole-resistantC. albicans. The discovery that ORI can effectively inhibit drug efflux and promote apoptosis may provide new insights and therapeutic strategies to overcome increasing azole resistance in C. albicans.
白色念珠菌是一种导致真菌感染的酵母，死亡率高，且通常对唑类药物具有耐药性。为了克服这种耐药性，我们探索了将冬凌草甲素（ORI）与三种唑类药物（氟康唑（FLC）、伊曲康唑（ITR）和伏立康唑（VOR））联合使用。唑类耐药的白色念珠菌菌株从癌症患者中获得，并研究了这些菌株的耐药逆转情况。
通过棋盘微量稀释法和时间杀伤试验来测量 ORI 和唑类药物的协同抗真菌活性。通过流式细胞术研究耐药逆转机制，即抑制药物外排和诱导细胞凋亡。通过 RT-qPCR 评估外排泵相关基因 CDR1 和 CDR2 的表达水平。
ORI 的外排泵抑制试验表明，氟康唑（128 倍）、伊曲康唑（64 倍）和伏立康唑（250 倍）的最小抑菌浓度（MIC）显著降低。耐药株中编码 CDR1 和 CDR2 的基因上调。ORI 对 FLC 治疗白色念珠菌的增敏作用还包括促进细胞凋亡。
我们证明了唑类药物与 ORI 联合使用具有强大的协同作用，并且 ORI 可以促进唑类耐药白色念珠菌对唑类药物的敏感性。发现 ORI 可以有效抑制药物外排并促进细胞凋亡，这可能为克服白色念珠菌中日益增加的唑类耐药性提供新的见解和治疗策略。
