AUTHOR=Yuan Rui , Tu Jie , Sheng Chunquan , Chen Xi , Liu Na 

TITLE=Effects of Hsp90 Inhibitor Ganetespib on Inhibition of Azole-Resistant Candida albicans

JOURNAL=Frontiers in Microbiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.680382

DOI=10.3389/fmicb.2021.680382

ISSN=1664-302X

ABSTRACT=<p><italic>Candida albicans</italic> is the most common fungal pathogen. Recently, drug resistance of <italic>C. albicans</italic> 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 <italic>C. albicans</italic>, the microdilution checkerboard method was used to measure the <italic>in vitro</italic> 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 <italic>C. albicans</italic> biofilm formation, filamentation, and efflux pump. Real-time RT-PCR analysis was employed to clarify the mechanism of antagonizing drug resistance. The <italic>in vivo</italic> antifungal efficacy of ganetespib was determined by the infectious model of azole-resistant <italic>C. albicans</italic>. Ganetespib showed an excellent synergistic antifungal activity <italic>in vitro</italic> and significantly inhibited the fungal biofilm formation, whereas it had no inhibitory effect on fungal hypha formation. Expression of azole-targeting enzyme gene <italic>ERG11</italic> and efflux pump genes <italic>CDR1, CDR2</italic>, and <italic>MDR1</italic> was significantly down-regulated when ganetespib was used in combination with FLC. In a mouse model infected with FLC-resistant <italic>C. albicans</italic>, the combination of ganetespib and FLC effectively reversed the FLC resistance and significantly decreased the kidney fungal load of mouse.</p>