Synthesis, Structure–Activity Relationship Study, Bioactivity, and Nephrotoxicity Evaluation of the Proposed Structure of the Cyclic Lipodepsipeptide Brevicidine B,Journal of Natural Products

当前位置： X-MOL 学术 › J. Nat. Prod. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Synthesis, Structure–Activity Relationship Study, Bioactivity, and Nephrotoxicity Evaluation of the Proposed Structure of the Cyclic Lipodepsipeptide Brevicidine B
Journal of Natural Products ( IF 3.3 ) Pub Date : 2024-02-29 , DOI: 10.1021/acs.jnatprod.3c00876
Dennise Palpal-Latoc _{1,

2,

3} , Aimee J Horsfall _{1,

2,

3} , Alan J Cameron _{1,

2,

3} , Georgia Campbell ₄ , Scott A Ferguson ₄ , Gregory M Cook ₄ , Veronika Sander ₅ , Alan J Davidson ₅ , Paul W R Harris _{1,

2,

3} , Margaret A Brimble _{1,

2,

3}

Affiliation

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.

中文翻译：

环状脂缩肽 Brevicidine B 拟定结构的合成、构效关系研究、生物活性和肾毒性评价

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 -Tyr ²到d -Phe ² ），并被命名为 brevicidine B ( 2 ) 。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，以我们之前报道的获得 brevicidine ( 1 ) 的合成策略为基础。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 -Phe ² ，产生对革兰氏阴性菌株无活性或仅表现出活性的类似物。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减轻毒性的策略。 brevicidine 的肾毒性。

更新日期：2024-02-29

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11