格尔德霉素和环孢素联合常用抗真菌药对阿萨希毛孢子菌临床株体外药敏研究

Effects of geldanamycin and cyclosporine combined with antifungal drugs against clinical Trichosporon asahii isolates in vitro

目的研究格尔德霉素和环孢素(热休克蛋白90与钙调磷酸酯酶抑制剂)抗阿萨希毛孢子菌活性,及联合常用抗真菌药物后的体外药物敏感性。方法通过美国临床实验室标准化协会(CLSI)推荐的M27-A3肉汤稀释法检测格尔德霉素和环孢素对21株阿萨希毛孢子菌临床株的体外抗真菌活性,棋盘微量液基稀释法检测上述2种抑制剂与5种常用抗真菌药(氟康唑、伊曲康唑、伏立康唑、两性霉素B和卡泊芬净)的相互作用。结果格尔德霉素对阿萨希毛孢子菌临床株有较好的体外抗真菌活性,而环孢素作用较弱。此外,格尔德霉素和环孢素与5种常用抗真菌药联合使用,均显示具有良好的体外抗阿萨希毛孢子菌协同作用。结论格尔德霉素和环孢素可以提高常用抗真菌药对阿萨希毛孢子菌的敏感性,提示一种针对侵袭性毛孢子菌病的潜在治疗策略。

Objective lnvasive trichosporonosis is associated with a high mortality rate and the emergence of MDR Trichosporon. Asahii（T. asahii） is of particular concern. Heat shock protein 90（Hsp90） and its client protein, calcineurin, represent an important pathway for fungal drug resistance. We investigated the antifungal activity of compounds targeting the Hsp90-calcineurin axis against T. asahii. Methods The in vitro antifungal activity of geldanamycin（the Hsp90 inhibitor） and cyclosporine A（anti-calcineurin drug） were assessed by the standard broth dilution method against 21 clinical isolates of T. asahii. Results Geldanamycin had good antifungal activity, while cyclosporine A had little antifungal activity against different T.asahii isolates. Moreover, both geldanamycin and cyclosporine A exhibited synergistic interactions with five antifungals（fluconazole, itraconazole, voriconazole, amphotericin B and caspofungin） against T. asahii. Conclusion lnhibitors targeting the Hsp90-calcineurin axis（geldanamycin and cyclosporine A） can increase the susceptibility of antifungals to T.asahii, which is suggested as a promising antifungal strategy against invasive trichosporonosis.