Lujuan Gao1, Yi Sun2, Chengyan He2, Ming Li1, Tongxiang Zeng2. 1. Department of Dermatology, Zhongshan Hospital Fudan University, Shanghai, China. 2. Department of Dermatology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, China.
Abstract
BACKGROUND: 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. OBJECTIVES: To investigate the antifungal effect of 17-AAG alone or combined with azoles against E. dermatitidis. METHODS: 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. RESULTS AND CONCLUSIONS: 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.
BACKGROUND: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. OBJECTIVES: To investigate the antifungal effect of 17-AAG alone or combined with azoles against E. dermatitidis. METHODS: 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. RESULTS AND CONCLUSIONS: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.