brevicidines 代表了一类新型非核糖体抗菌肽，对高度问题和耐药的革兰氏阴性病原菌具有显着的效力和选择性。最近发现的 brevicidine 家族成员，被命名为 brevicidine B (2)，在 brevicidine (1) 的线性部分的氨基酸序列中包含单个氨基酸取代（从 d-Tyr2 变为 d-Phe2），据报道，对革兰氏阴性 (MIC = 2-4 μgmL-1) 和革兰氏阳性 (MIC = 2-8 μgmL-1) 病原体表现出更广泛的抗菌活性。受此鼓舞，我们在此报告了 brevicidine B (2) 拟议结构的首次全合成，以我们之前报道的 brevicidine 合成策略 (1) 为基础。令人高兴的是，与原始分离纸一致，合成 2 对大肠杆菌、铜绿假单胞菌和肺炎克雷伯菌具有抗菌活性 (MIC = 4-8 μgmL-1)。然而有趣的是，synthetic 2 对所有测试的革兰氏阳性病原体均无活性，包括耐甲氧西林金黄色葡萄球菌菌株。用其对映体和其他疏水残基取代 d-Phe2，产生的类似物对革兰氏阴性菌株没有活性或仅表现出活性。与报道的天然化合物相比，我们的合成 2 的生物活性存在显着差异，因此需要重新评估原始天然产物的纯度或相对构型可能存在的差异。最后，在人肾类器官肾毒性模型中对合成 1 和 2 的评估显示，这两种化合物均具有显着毒性，尽管 1 的毒性低于 2 和多粘菌素 B。这些结果表明，对位置 2 的修饰可能提供一种策略来减轻brevicidine 的肾毒性。

The brevicidines represent a novel class of nonribosomal antimicrobial peptides that possess remarkable potency and selectivity toward highly problematic and resistant Gram-negative pathogenic bacteria. A recently discovered member of the brevicidine family, coined brevicidine B (2), comprises a single amino acid substitution (from d-Tyr2 to d-Phe2) in the amino acid sequence of the linear moiety of brevicidine (1) and was reported to exhibit broader antimicrobial activity against both Gram-negative (MIC = 2-4 μgmL-1) and Gram-positive (MIC = 2-8 μgmL-1) pathogens. Encouraged by this, we herein report the first total synthesis of the proposed structure of brevicidine B (2), building on our previously reported synthetic strategy to access brevicidine (1). In agreement with the original isolation paper, pleasingly, synthetic 2 demonstrated antimicrobial activity toward Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae (MIC = 4-8 μgmL-1). Interestingly, however, synthetic 2 was inactive toward all of the tested Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus strains. Substitution of d-Phe2 with its enantiomer, and other hydrophobic residues, yields analogues that were either inactive or only exhibited activity toward Gram-negative strains. The striking difference in the biological activity of our synthetic 2 compared to the reported natural compound warrants the re-evaluation of the original natural product for purity or possible differences in relative configuration. Finally, the evaluation of synthetic 1 and 2 in a human kidney organoid model of nephrotoxicity revealed substantial toxicity of both compounds, although 1 was less toxic than 2 and polymyxin B. These results indicate that modification to position 2 may afford a strategy to mitigate the nephrotoxicity of brevicidine.