Rapamycin and less immunosuppressive analogs are toxic to Candida albicans and Cryptococcus neoformans via FKBP12-dependent inhibition of TOR
Rapamycin and less immunosuppressive analogs are toxic to Candida albicans and Cryptococcus neoformans via FKBP12-dependent inhibition of TOR
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DOI：
10.1128/aac.45.11.3162-3170.2001
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发表时间：
2001-11-01
影响因子：
4.9
通讯作者：
Heitman, J
中科院分区：
文献类型：
--
作者：
Cruz, MC;Goldstein, AL;Heitman, J
白色念珠菌和新型隐球菌可引起人类浅表性和弥散性感染。目前深部感染的抗真菌治疗仅限于两性霉素B、氟胞嘧啶和唑类药物。一个限制是常用的唑类药物在体内和体外都有抑菌作用。我们的研究探讨了免疫抑制药物雷帕霉素（西罗莫司）及其免疫抑制活性降低的类似物的抗真菌活性机制。白色念珠菌rbp1/rbp1突变株缺乏fk506 -雷帕霉素靶蛋白FKBP12的同源物，对雷帕霉素及其类似物具有抗性。雷帕霉素和类似物促进FKBP12与野生型Tor1激酶结合，但不与耐雷帕霉素的Tor1突变激酶结合（S1972R）。FKBP12和TOR突变使白色念珠菌、新生念珠菌和酿酒酵母菌对雷帕霉素及其类似物产生耐药性。我们的研究结果表明，雷帕霉素和雷帕霉素类似物的抗真菌活性是通过在不同酵母中与FKBP12和Tor激酶同源物的保守复合物介导的。结合我们的观察，雷帕霉素及其类似物具有杀真菌作用，自发耐药性发生率低，这些机制发现支持继续研究雷帕霉素类似物作为新型抗真菌药物。
Candida albicans and Cryptococcus neoformans cause both superficial and disseminated infections in humans. Current antifungal therapies for deep-seated infections are limited to amphotericin B, flucytosine, and azoles. A limitation is that commonly used azoles are fungistatic in vitro and in vivo. Our studies address the mechanisms of antifungal activity of the immunosuppressive drug rapamycin (sirolimus) and its analogs with decreased immunosuppressive activity. C. albicans rbp1/rbp1 mutant strains lacking a homolog of the FK506-rapamycin target protein FKBP12 were found to be viable and resistant to rapamycin and its analogs. Rapamycin and analogs promoted FKBP12 binding to the wild-type Tor1 kinase but not to a rapamycin-resistant Tor1 mutant kinase (S1972R). FKBP12 and TOR mutations conferred resistance to rapamycin and its analogs in C. albicans, C. neoformans, and Saccharomyces cerevisiae. Our findings demonstrate the antifungal activity of rapamycin and rapamycin analogs is mediated via conserved complexes with FKBP12 and Tor kinase homologs in divergent yeasts. Taken together with our observations that rapamycin and its analogs are fungicidal and that spontaneous drug resistance occurs at a low rate, these mechanistic findings support continued investigation of rapamycin analogs as novel antifungal agents.