Signaling cascades as drug targets in model and pathogenic fungi.
Signaling cascades as drug targets in model and pathogenic fungi.
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发表时间：
2008-08
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通讯作者：
R. Bastidas;J. Reedy;Helena Morales-Johansson;J. Heitman;M. Cárdenas
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作者：
R. Bastidas;J. Reedy;Helena Morales-Johansson;J. Heitman;M. Cárdenas
微生物进化成天然产物，抑制竞争对手土壤微生物的生长。在许多情况下，这些化合物对真菌起作用，真菌是真核生物，具有与后生动物(包括人类)密切相关的保守基因序列。钙调神经磷酸酶抑制剂环孢素A和FK-506，Tor抑制剂雷帕霉素和Hsp90抑制剂格尔达那霉素，都是通过从酵母到人类的保守靶点发挥作用的。这使得可以使用遗传上易处理的真菌作为模型来阐明这些药物及其靶点如何在酵母和人类细胞中发挥作用。这些抑制剂还使旨在利用其内在抗菌活性的研究能够开发新的抗真菌疗法。广泛的研究表明，Tor蛋白在全球范围内具有保守的作用，调节生长和增殖以响应营养，并针对其基本功能导致强大的抗真菌作用。同样，钙调神经磷酸酶在真菌毒力中的保守和关键作用已被确立，并可作为抑制剂在各种临床环境中用于治疗的靶点。最后，钙调神经磷酸酶或热休克蛋白90的抑制剂与唑类或葡聚糖合成酶抑制剂(坎迪斯)具有显著的协同作用，这一发现提供了另一个治疗优势。综上所述，这些真菌靶点及其抑制剂为开发新型抗菌疗法提供了一个强大的平台。
Microbes evolved to produce natural products that inhibit growth of competing soil microorganisms. In many cases these compounds act on fungi, which are eukaryotes with conserved gene sequences closely related to metazoans, including humans. The calcineurin inhibitors cyclosporin A and FK-506, the Tor inhibitor rapamycin, and the Hsp90 inhibitor geldanamycin, all act via targets conserved from yeast to humans. This allows the use of genetically tractable fungi as models to elucidate how these drugs and their targets function in yeast and human cells. These inhibitors also enable studies aimed at harnessing their intrinsic antimicrobial activities to develop novel antifungal therapies. Extensive studies have revealed a globally conserved role for the Tor protein in regulating growth and proliferation in response to nutrients, and targeting its essential functions results in robust antifungal action. Similarly, a conserved and essential role for calcineurin in fungal virulence has been established and could be targeted by inhibitors for therapeutic uses in a variety of clinical settings. Finally, the discovery that inhibitors of calcineurin or Hsp90 result in dramatic synergism with either azoles or glucan synthase inhibitors (candins) provides another therapeutic vantage point. Taken together, these fungal targets and their inhibitors provide a robust platform from which to develop novel antimicrobial therapies.