Department of Microbial Biotechnology and Cell Biology, Faculty of Science and Technology, University of Debrecen, 4032 Debrecen, Hungary.
Appl Microbiol Biotechnol. 2013 Apr;97(8):3267-84. doi: 10.1007/s00253-013-4761-9. Epub 2013 Mar 6.
The first echinocandin-type antimycotic (echinocandin B) was discovered in the 1970s. It was followed by the isolation of more than 20 natural echinocandins. These cyclic lipo-hexapeptides are biosynthesized on non-ribosomal peptide synthase complexes by different ascomycota fungi. They have a unique mechanism of action; as non-competitive inhibitors of β-1,3-glucan synthase complex they target the fungal cell wall. Results of the structure-activity relationship experiments let us develop semisynthetic derivatives with improved properties. Three cyclic lipohiexapeptides (caspofungin, micafungin and anidulafungin) are currently approved for use in clinics. As they show good fungicidal (Candida spp.) or fungistatic (Aspergillus spp.) activity against the most important human pathogenic fungi including azole-resistant strains, they are an important addition to the antifungal armamentarium. Some evidence of acquired resistance against echinocandins has been detected among Candida glabrata strains in recent years, which enhanced the importance of data collected on the mechanism of acquired resistance developing against the echinocandins. In this review, we show the structural diversity of natural echinocandins, and we summarize the emerging data on their mode of action, biosynthesis and industrial production. Their clinical significance as well as the mechanism of natural and acquired resistance is also discussed.
第一个棘白菌素类抗真菌药物（棘白菌素 B）于 20 世纪 70 年代被发现。随后，又分离出了 20 多种天然棘白菌素。这些环状脂六肽是由不同的子囊菌真菌在非核糖体肽合成酶复合物上生物合成的。它们具有独特的作用机制；作为β-1,3-葡聚糖合成酶复合物的非竞争性抑制剂，它们作用于真菌细胞壁。结构-活性关系实验的结果使我们能够开发出具有改良特性的半合成衍生物。三种环状脂六肽（卡泊芬净、米卡芬净和阿尼芬净）目前已获准在临床上使用。由于它们对包括唑类耐药株在内的最重要的人类致病真菌具有良好的杀菌（念珠菌属）或抑菌（曲霉属）活性，因此它们是抗真菌武器库的重要补充。近年来，在光滑念珠菌菌株中已经检测到对棘白菌素类药物获得性耐药的证据，这增强了对抗棘白菌素类药物获得性耐药机制收集数据的重要性。在这篇综述中，我们展示了天然棘白菌素的结构多样性，并总结了关于它们的作用机制、生物合成和工业生产的新出现的数据。还讨论了它们的临床意义以及天然和获得性耐药的机制。
