Teixobactin analogues reveal enduracididine to be non-essential for highly potent antibacterial activity and lipid II binding.
Teixobactin analogues reveal enduracididine to be non-essential for highly potent antibacterial activity and lipid II binding.
复制标题
DOI：
10.1039/c7sc03241b
复制
发表时间：
2017-12-01
期刊：
影响因子：
8.4
通讯作者：
Singh I
中科院分区：
文献类型：
--
作者：
Parmar A;Iyer A;Prior SH;Lloyd DG;Leng Goh ET;Vincent CS;Palmai-Pallag T;Bachrati CZ;Breukink E;Madder A;Lakshminarayanan R;Taylor EJ;Singh I
Leu 10-teixobactin和Ile 10-teixobactin显示出与天然teixobactin相当的活性。泰素菌素是一种由四个d-氨基酸和一个罕见的l-异丙酰氨基酸组成的具有很高应用前景的抗菌缩肽。据报道，l-别洛-Enduracidine对于teixobactin的高效抗菌活性非常重要。然而，它也是开发有效的teixobactin类似物的关键限制因素，这是由于几个合成挑战，例如它不是市售的，需要多步合成，长时间和重复偶联（16-30小时）。由于所有这些挑战，teixobactin的全合成是费力的并且产率低（3.3%）。在这项工作中，我们已经确定了一种独特的设计，并开发了一种快速合成（每个氨基酸10分钟μ波辅助偶联，30分钟环化）的几种高效的替沙菌素类似物，产率为10-24%，通过用商业上可获得的非极性残基如亮氨酸和异亮氨酸取代l-异丙酰亚胺。最重要的是，Leu 10-teixobactin和Ile 10-teixobactin类似物对更广泛的MRSA和粪肠球菌（VRE）显示出高效的抗菌活性。此外，尽管这些合成类似物的设计更简单且易于合成，但它们对MRSA ATCC 33591显示出与天然替沙菌素相同的抗菌活性（MIC 0.25 μg mL-1）。我们已经证实了脂质II结合，并通过NMR测量了Ala 10-teixobactin对焦磷酸香叶酯的单个氨基酸残基的结合亲和力，以了解结合相互作用的性质和强度。与目前的理解相反，我们已经表明，在位置10的阳离子氨基酸是不是必不可少的目标（脂质II）的结合和有效的抗菌活性的teixobactin。因此，我们提供了强有力的证据，与关于这种令人兴奋的新抗生素作用机制的许多假设相反。在位置10处引入非阳离子残基允许在设计和合成高度有效的替沙菌素类似物方面的巨大多样化，并为开发替沙菌素类似物作为靶向MRSA和结核分枝杆菌的新型药物样分子奠定了基础。
Leu10-teixobactin and Ile10-teixobactin have shown comparable activity to natural teixobactin. Teixobactin is a highly promising antibacterial depsipeptide consisting of four d-amino acids and a rare l-allo-enduracididine amino acid. l-allo-Enduracididine is reported to be important for the highly potent antibacterial activity of teixobactin. However, it is also a key limiting factor in the development of potent teixobactin analogues due to several synthetic challenges such as it is not commercially available, requires a multistep synthesis, long and repetitive couplings (16–30 hours). Due to all these challenges, the total synthesis of teixobactin is laborious and low yielding (3.3%). In this work, we have identified a unique design and developed a rapid synthesis (10 min μwave assisted coupling per amino acid, 30 min cyclisation) of several highly potent analogues of teixobactin with yields of 10–24% by replacing the l-allo-enduracididine with commercially available non-polar residues such as leucine and isoleucine. Most importantly, the Leu10-teixobactin and Ile10-teixobactin analogues have shown highly potent antibacterial activity against a broader panel of MRSA and Enterococcus faecalis (VRE). Furthermore, these synthetic analogues displayed identical antibacterial activity to natural teixobactin (MIC 0.25 μg mL–1) against MRSA ATCC 33591 despite their simpler design and ease of synthesis. We have confirmed lipid II binding and measured the binding affinities of individual amino acid residues of Ala10-teixobactin towards geranyl pyrophosphate by NMR to understand the nature and strength of binding interactions. Contrary to current understanding, we have shown that a cationic amino acid at position 10 is not essential for target (lipid II) binding and potent antibacterial activity of teixobactin. We thus provide strong evidence contrary to the many assumptions made about the mechanism of action of this exciting new antibiotic. Introduction of a non-cationic residue at position 10 allows for tremendous diversification in the design and synthesis of highly potent teixobactin analogues and lays the foundations for the development of teixobactin analogues as new drug-like molecules to target MRSA and Mycobacterium tuberculosis.
登录
查看更多内容
影响因子：
2.7
作者：
Atkinson DJ;Naysmith BJ;Furkert DP;Brimble MA
通讯作者：
Brimble MA
影响因子：
4.1
作者：
Abdel Monaim SAH;Jad YE;Ramchuran EJ;El-Faham A;Govender T;Kruger HG;de la Torre BG;Albericio F
通讯作者：
Albericio F
影响因子：
16.8
作者：
Hsu, STD;Breukink, E;van Nuland, NAJ
通讯作者：
van Nuland, NAJ
溶酶体的作用机理。
影响因子：
15
作者：
Lee W;Schaefer K;Qiao Y;Srisuknimit V;Steinmetz H;Müller R;Kahne D;Walker S
通讯作者：
Walker S
teixobactin 类似物的 X 射线晶体结构揭示了 teixobactin 药效团的关键相互作用。
DOI：
10.1039/c7cc00783c
发表时间：
2017-02-28
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Yang H;Du Bois DR;Ziller JW;Nowick JS
通讯作者：
Nowick JS