Abstract
Candida albicans is the most common fungal pathogen. Recently, drug resistance of C. albicans is increasingly severe. Hsp90 is a promising antifungal target to overcome this problem. To evaluate the effects of Hsp90 inhibitor ganetespib on the inhibition of azole-resistant C. albicans, the microdilution checkerboard method was used to measure the in vitro synergistic efficacy of ganetespib. The XTT/menadione reduction assay, microscopic observation, and Rh6G efflux assay were established to investigate the effects of ganetespib on azole-resistant C. albicans biofilm formation, filamentation, and efflux pump. Real-time RT-PCR analysis was employed to clarify the mechanism of antagonizing drug resistance. The in vivo antifungal efficacy of ganetespib was determined by the infectious model of azole-resistant C. albicans. Ganetespib showed an excellent synergistic antifungal activity in vitro and significantly inhibited the fungal biofilm formation, whereas it had no inhibitory effect on fungal hypha formation. Expression of azole-targeting enzyme gene ERG11 and efflux pump genes CDR1, CDR2, and MDR1 was significantly down-regulated when ganetespib was used in combination with FLC. In a mouse model infected with FLC-resistant C. albicans, the combination of ganetespib and FLC effectively reversed the FLC resistance and significantly decreased the kidney fungal load of mouse.
Highlights
Invasive fungal infections (IFIs) are emerging as a severe threat in the clinic due to the increasing number of immune-impaired patients (Miceli et al, 2011; Brown et al, 2012)
Four Heat shock protein 90 (Hsp90) inhibitors had no direct effect on the growth of azole-resistant C. albicans (MIC80 > 64 μg/mL)
Time–growth curve revealed that the growth of azole-resistant C. albicans was inhibited obviously using the combination of ganetespib and FLC (8+8 μg/mL, Supplementary Figure 1)
Summary
Invasive fungal infections (IFIs) are emerging as a severe threat in the clinic due to the increasing number of immune-impaired patients (Miceli et al, 2011; Brown et al, 2012). Candida albicans (C. albicans) is the most common fungal pathogen in IFIs. Currently, only three classes of antifungal drugs are available for the treatment of infectious C. albicans: polyenes (e.g., amphotericin B), azoles (e.g., fluconazole), and echinocandins (e.g., caspofungin). Azoles are the first-line clinical drugs used to treat IFIs. Extensive and prophylactic use of antifungal agents, especially azoles, could lead to the emergence of fungal resistance, which has become a serious concern (Odds, 2005; Perfect, 2017). The resistance problem is severe in Candida species (Revie et al, 2018). There is an urgent need to explore new treatments for resistant candidiasis
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