Herein we report the antibacterial structure-activity relationships of cyclic hexapeptide wollamide analogs derived from solid-phase library synthesis. Wollamide B, a cyclic hexapeptide natural product, has been previously found to have activity against Mycobacterium bovis. To further evaluate its antimycobacterial/antibacterial potential, 27 peptides including wollamides A/B, and desotamide B, were synthesized and subsequently tested against a panel of clinically significant bacterial pathogens. Biological evaluation revealed that the cyclic scaffold, amide functionality in position I, tryptophan residue in position V, and the original stereochemistry pattern of the core scaffold were key for antituberculosis and/or antibacterial activity. In addition, against M. tuberculosis and Gram-positive bacteria, residues in position II and/or VI greatly impacted antibacterial activity and selectivity. Wollamides A (3) and B (2) along with their corresponding II (l-Leu) analog 10 retained the most promising antituberculosis activity, with the lowest minimum inhibitory concentration (MIC) against virulent M. tuberculosis H37Rv (MIC = 1.56 μg/mL), as well as desirable selectivity indices (>100). Importantly, the antimicrobial activities of wollamides A and B do not result from disruption of the bacterial membrane, warranting further investigation into their mechanism of action.

中文翻译：

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环六肽Wollamide B类似物的固相合成和抗菌活性。

在本文中，我们报道了衍生自固相文库合成的环状六肽wollamide类似物的抗菌结构-活性关系。先前已经发现，环状六肽天然产物Wollamide B对牛分枝杆菌具有活性。为了进一步评估其抗分枝杆菌/抗菌潜力，合成了27种肽，包括wollamides A / B和desotamide B，然后针对一组临床上重要的细菌病原体进行了测试。生物学评估表明，环状支架，位置I的酰胺官能团，位置V的色氨酸残基以及核心支架的原始立体化学模式是抗结核和/或抗菌活性的关键。此外，针对结核分枝杆菌和革兰氏阳性菌，II和/或VI位的残基极大地影响了抗菌活性和选择性。Wollamides A（3）和B（2）以及它们相应的II（l-Leu）类似物10保留了最有希望的抗结核病活性，对强毒结核分枝杆菌H37Rv的最低抑菌浓度（MIC）最低（MIC = 1.56μg/毫升）以及所需的选择性指数（> 100）。重要的是，沃尔拉米德A和B的抗微生物活性不是由细菌膜破坏引起的，因此有必要对其作用机理进行进一步研究。结核H37Rv（MIC = 1.56μg/ mL），以及理想的选择性指数（> 100）。重要的是，沃尔拉米德A和B的抗微生物活性不是由细菌膜破坏引起的，因此有必要对其作用机理进行进一步研究。结核H37Rv（MIC = 1.56μg/ mL），以及理想的选择性指数（> 100）。重要的是，沃尔拉米德A和B的抗微生物活性不是由细菌膜破坏引起的，因此有必要对其作用机理进行进一步研究。