Ergosterol biosynthesis inhibitors become fungicidal when combined with calcineurin inhibitors against Candida albicans, Candida glabrata, and Candida krusei
Ergosterol biosynthesis inhibitors become fungicidal when combined with calcineurin inhibitors against Candida albicans, Candida glabrata, and Candida krusei
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DOI：
10.1128/aac.47.3.956-964.2003
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发表时间：
2003-03-01
影响因子：
4.9
通讯作者：
Heitman, J
中科院分区：
文献类型：
--
作者：
Onyewu, C;Blankenship, JR;Heitman, J
唑类化合物以麦角甾醇生物合成酶羊毛甾醇14α-脱甲基酶为靶标，因其治疗窗口广、活性范围广、毒性低而被广泛应用于抗真菌药物中。不幸的是，唑类药物通常具有抗真菌作用，并且在几种真菌病原体中出现了对氟康唑的抗药性。我们最近发现，蛋白磷酸酶钙调神经磷酸酶允许白色念珠菌在唑类药物施加的膜压力下存活。钙调神经磷酸酶抑制剂环孢素A(CsA)和他克莫司(FK506)与唑类化合物有很强的协同作用，具有很强的杀菌活性，而钙调神经磷酸酶缺失的突变株对氮唑类药物高度敏感。在这里，我们建立了针对麦角固醇生物合成途径中其他酶的药物(特比奈芬和芬普莫芬)，当与CsA和FK506联合使用时，也显示出显著的协同抗真菌活性。同样，缺乏钙调神经磷酸酶B的白色念珠菌突变株对特比奈芬和芬普莫芬明显过敏。FK506结合蛋白FKBP12是FK506与麦角甾醇生物合成抑制剂协同作用所必需的，而导致FK506耐药的钙调神经磷酸酶突变取消了药物协同作用。此外，我们提供了非免疫抑制的FK506类似物L-685,818与芬普莫芬或特比奈芬之间对抗野生型白色念珠菌的药物协同作用的证据。这些药物组合还对另外两个念珠菌物种发挥协同作用，光滑念珠菌和克鲁斯念珠菌是已知的固有或迅速获得的对唑类药物的耐药性。这些研究表明，通过抑制钙调神经磷酸酶信号通路，扩大其作用范围，为克服抗真菌药物的耐药性提供了一种替代方法，从而提高了以麦角甾醇生物合成为靶点的非唑类抗真菌药物的活性。
Azoles target the ergosterol biosynthetic enzyme lanosterol 14alpha-demethylase and are a widely applied class of antifungal agents because of their broad therapeutic window, wide spectrum of activity, and low toxicity. Unfortunately, azoles are generally fungistatic and resistance to fluconazole is emerging in several fungal pathogens. We recently established that the protein phosphatase calcineurin allows survival of Candida albicans during the membrane stress exerted by azoles. The calcineurin inhibitors cyclosporine A (CsA) and tacrolimus (FK506) are dramatically synergistic with azoles, resulting in potent fungicidal activity, and mutant strains lacking calcineurin are markedly hypersensitive to azoles. Here we establish that drugs targeting other enzymes in the ergosterol biosynthetic pathway (terbinafine and fenpropimorph) also exhibit dramatic synergistic antifungal activity against wild-type C. albicans when used in conjunction with CsA and FK506. Similarly, C. albicans mutant strains lacking calcineurin B are markedly hypersensitive to terbinafine and fenpropimorph. The FK506 binding protein FKBP12 is required for FK506 synergism with ergosterol biosynthesis inhibitors, and a calcineurin mutation that confers FK506 resistance abolishes drug synergism. Additionally, we provide evidence of drug synergy between the nonimmunosuppressive FK506 analog L-685,818 and fenpropimorph or terbinafine against wild-type C. albicans. These drug combinations also exert synergistic effects against two other Candida species, C. glabrata and C. krusei, which are known for intrinsic or rapidly acquired resistance to azoles. These studies demonstrate that the activity of non-azole antifungal agents that target ergosterol biosynthesis can be enhanced by inhibition of the calcineurin signaling pathway, extending their spectrum of action and providing an alternative approach by which to overcome antifungal drug resistance.