Department of Dermatology, Zhongshan Hospital Fudan University, Shanghai, China.
Department of Dermatology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, China.
Mycoses. 2018 Nov;61(11):853-856. doi: 10.1111/myc.12824. Epub 2018 Jul 27.
Exophiala dermatitidis causes a variety of illnesses in humans which are always refractory to available treatment modalities. Hsp90 governs crucial stress responses, cell wall repair mechanisms and antifungal resistance in pathogenic fungi. Thus, targeting Hsp90 with specific inhibitors holds considerable promise as combination strategy.
To investigate the antifungal effect of 17-AAG alone or combined with azoles against E. dermatitidis.
In vitro interactions of 17-AAG, a Hsp90 inhibitor, and azoles including itraconazole, voriconazole and posaconazole against E. dermatitidis were evaluated via broth microdilution chequerboard technique, adapted from the CLSI M38-A2 method. A total of 18 clinical strains were studied. Candida parapsilosis (ATCC22019) was included to ensure quality control.
17-AAG alone exhibited minimal antifungal activity against all tested isolates. However, synergistic effects between 17-AAG and posaconazole, itraconazole or voriconazole were observed against 15 (83.3%), 12 (66.7%) and 1 (5.6%) isolates of E. dermatitidis, respectively. The effective working ranges of 17-AAG in synergistic combinations were mostly within 2-8 μg/mL. No antagonism was observed. In conclusion, harnessing fungal Hsp90 with 17-AAG might prove a potential antifungal regimen for E. dermatitidis infections. However, due to the host toxicity of 17-AAG, more efforts are needed to develop fungal specific Hsp90 inhibitors.
外瓶霉可引起人类多种疾病，且对现有治疗方法均具有抗药性。Hsp90 调控着致病性真菌中的关键应激反应、细胞壁修复机制和抗真菌耐药性。因此，采用特异性抑制剂靶向 Hsp90 具有相当大的应用前景，可作为联合治疗策略。
研究 17-AAG 单独或与唑类药物联合对皮炎外瓶霉的抗真菌作用。
采用 CLSI M38-A2 方法改编的肉汤微量稀释棋盘法，评估 Hsp90 抑制剂 17-AAG 与唑类药物（伊曲康唑、伏立康唑和泊沙康唑）单独或联合对皮炎外瓶霉的体外相互作用。共研究了 18 株临床分离株，包括近平滑念珠菌（ATCC22019）作为质量控制。
17-AAG 单独对所有测试分离株的抗真菌活性均较弱。然而，17-AAG 与泊沙康唑、伊曲康唑或伏立康唑联合使用时，分别对 15（83.3%）、12（66.7%）和 1（5.6%）株皮炎外瓶霉表现出协同作用。17-AAG 在协同组合中的有效工作范围多在 2-8μg/mL 之间。未观察到拮抗作用。综上所述，利用真菌 Hsp90 与 17-AAG 联合可能成为治疗皮炎外瓶霉感染的潜在抗真菌方案。然而，由于 17-AAG 的宿主毒性，还需要进一步努力开发真菌特异性 Hsp90 抑制剂。
