Division of Molecular Materials Science, Graduate School of Science, Osaka City University, Sumiyoshi-ku, Osaka 558-8585, Japan.
Bioorg Med Chem. 2011 Sep 15;19(18):5300-10. doi: 10.1016/j.bmc.2011.08.010. Epub 2011 Aug 11.
Cyclothiazomycin B1 (CTB1) is an antifungal cyclic thiopeptide isolated from the culture broth of Streptomyces sp. HA 125-40. CTB1 inhibited the growth of several filamentous fungi including plant pathogens along with swelling of hyphae and spores. The antifungal activity of CTB1 was weakened by hyperosmotic conditions, and hyphae treated with CTB1 burst under hypoosmotic conditions, indicating increased cell wall fragility. CTB1-sensitive fungal species contain high levels of cell wall chitin and/or chitosan. Unlike nikkomycin Z, a competitive inhibitor of chitin synthase (CHS), CTB1 did not inhibit CHS activity. Although CTB1 inhibited CHS biosynthesis, the same result was also obtained with a non-specific proteins inhibitor, cycloheximide, which did not reduce cell wall rigidity. These results indicate that the primary target of CTB1 is not CHS, and we concluded that CTB1 antifungal activity was independent of this sole inhibition. We found that CTB1 bound to chitin but did not bind to β-glucan and chitosan. The results of the present study suggest that CTB1 induces cell wall fragility by binding to chitin, which forms the fungal cell wall. The antifungal activity of CTB1 could be explained by this chitin-binding ability.
环噻唑霉素 B1（CTB1）是从链霉菌 sp. HA 125-40 的发酵液中分离得到的一种抗真菌环硫肽。CTB1 抑制了几种丝状真菌的生长，包括植物病原体，同时还导致菌丝和孢子肿胀。CTB1 的抗真菌活性在高渗条件下减弱，而在低渗条件下用 CTB1 处理的菌丝会破裂，表明细胞壁脆弱性增加。CTB1 敏感的真菌物种含有高水平的细胞壁几丁质和/或壳聚糖。与几丁质合成酶（CHS）的竞争性抑制剂 nikkomycin Z 不同，CTB1 不抑制 CHS 活性。尽管 CTB1 抑制 CHS 生物合成，但同样的结果也可以用非特异性蛋白质抑制剂环己酰亚胺获得，而环己酰亚胺不会降低细胞壁刚性。这些结果表明 CTB1 的主要靶标不是 CHS，我们得出结论，CTB1 的抗真菌活性不是仅通过这种抑制作用产生的。我们发现 CTB1 与几丁质结合，但不与β-葡聚糖和壳聚糖结合。本研究的结果表明，CTB1 通过与构成真菌细胞壁的几丁质结合来诱导细胞壁脆弱性。CTB1 的抗真菌活性可以用这种几丁质结合能力来解释。
