Debono M, Gordee R S
Natural Products Research Division, Eli Lilly and Company, Indianapolis, Indiana 46285.
Annu Rev Microbiol. 1994;48:471-97. doi: 10.1146/annurev.mi.48.100194.002351.
The discovery of antifungal agents that possess selective toxicity against the eukaryotic fungal cell remains an important scientific challenge. The growing medical need for safe and effective antifungal agents stems from the rapidly increasing population of immunocompromised patients. Although the treatment of fungal infections is progressing steadily, currently available agents act on targets that are also found in mammalian cells. Ideally, a selectively toxic antifungal agent should be developed that interacts with a fungal target not found in other eukaryotic cells. This strategy involves selective inhibition of the biosynthesis of important structural elements in the fungal cell. The fungal cell wall is such a therapeutic target. In addition, antibiotics have been discovered that inhibit the development of the fungal cell. The major targets are glucan synthesis, inhibited by the echinocandin lipopeptides and the papulacandins; chitin synthesis, inhibited by the polyoxins and nikkomycins; and mannan, to which the pradimicins selectively bind. The extensively studied echinocandin lipopeptides are fungicidal agents with low toxicity, and one member, cilofungin--a semisynthetic analogue of echinocandin B--has been tested in the clinic. Newer echinocandins, such as LY303366 and the pneumocandins, have excellent activity against yeasts and Pneumocystis carinii infections in animals and show promise as potential clinical antifungal candidates. Chitin synthase inhibitors have been studied through chemical modification of the polyoxins and nikkomycins but are limited because of unfavorable pharmacokinetics. The pradimicins show the ability to bind mannan and thus exert an antifungal effect. The mode of action of this class of inhibitors is not fully understood, but their unique action may provide a better understanding of mannan as a target.
发现对真核真菌细胞具有选择性毒性的抗真菌剂仍然是一项重大的科学挑战。对安全有效的抗真菌剂的医疗需求不断增长，这源于免疫功能低下患者数量的迅速增加。尽管真菌感染的治疗正在稳步进展，但目前可用的药物作用于哺乳动物细胞中也存在的靶点。理想情况下，应开发一种选择性毒性抗真菌剂，使其与其他真核细胞中不存在的真菌靶点相互作用。这种策略涉及选择性抑制真菌细胞中重要结构成分的生物合成。真菌细胞壁就是这样一个治疗靶点。此外，还发现了抑制真菌细胞发育的抗生素。主要靶点包括：被棘白菌素脂肽和丘疹霉素抑制的葡聚糖合成；被多氧霉素和尼克霉素抑制的几丁质合成；以及普拉地米星选择性结合的甘露聚糖。经过广泛研究的棘白菌素脂肽是低毒性的杀真菌剂，其中一个成员西洛芬净（棘白菌素B的半合成类似物）已在临床上进行了测试。新型棘白菌素，如LY303366和肺孢菌素，对动物体内的酵母菌和卡氏肺孢子虫感染具有优异的活性，并有望成为潜在的临床抗真菌候选药物。几丁质合酶抑制剂已通过对多氧霉素和尼克霉素进行化学修饰进行了研究，但由于药代动力学不佳而受到限制。普拉地米星显示出结合甘露聚糖并因此发挥抗真菌作用的能力。这类抑制剂的作用模式尚未完全了解，但其独特作用可能有助于更好地理解甘露聚糖作为一个靶点的情况。
