Total Synthesis and Functional Evaluation of Fourteen Derivatives of Lysocin E: Importance of Cationic, Hydrophobic, and Aromatic Moieties for Antibacterial Activity
Total Synthesis and Functional Evaluation of Fourteen Derivatives of Lysocin E: Importance of Cationic, Hydrophobic, and Aromatic Moieties for Antibacterial Activity
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DOI：
10.1002/chem.201604022
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发表时间：
2016-11-01
影响因子：
4.3
通讯作者：
Inoue，Masayuki
中科院分区：
文献类型：
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作者：
Kaji，Takuya;Murai，Motoki;Inoue，Masayuki
Lysocin E（1）是一种结构复杂的37元缩肽，包含12个氨基酸残基，具有N-甲基化酰胺和酯键。 化合物1与细菌膜中的甲萘醌（MK）结合以发挥其有效的杀菌活性。为了破译这种独特抗生素中的生物学重要功能，我们通过系统地改变l-Thr-1，d-Arg-2，N-Me-d-Phe-5，d-Arg-7，l-Glu-8和d-Trp-10的侧链结构进行了全面的结构活性关系（SAR）研究。首先，我们采用固相合成策略全合成了14个新的1的侧链类似物。然后，我们评估了MK依赖性脂质体破坏和对金黄色葡萄球菌1及其类似物的抗菌活性。脂质体与细菌实验的相关数据表明，膜裂解是脂质体抑菌的主要机制。将d-Arg-2/7的阳离子胍部分改变为中性酰胺，并且将l-Thr-1的C7-酰基改变为C2或C11对应物，使抗微生物活性降低四倍或八倍。更严重的是，d ‐Trp‐10至od ‐Ala‐10的化学突变完全消除了生物活性。这些重要的发现使我们提出了侧链功能的生物学作用。
Lysocin E (1) is a structurally complex 37‐membered depsipeptide comprising 12 amino‐acid residues with an N‐methylated amide and an ester linkage. Compound1binds to menaquinone (MK) in the bacterial membrane to exert its potent bactericidal activity. To decipher the biologically important functionalities within this unique antibiotic, we performed a comprehensive structure‐activity relationship (SAR) study by systematically changing the side‐chain structures ofl‐Thr‐1,d‐Arg‐2, N‐Me‐d‐Phe‐5,d‐Arg‐7,l‐Glu‐8, andd‐Trp‐10. First, we achieved total synthesis of the 14 new side‐chain analogues of1by employing a solid‐phase strategy. We then evaluated the MK‐dependent liposomal disruption and antimicrobial activity againstStaphylococcus aureusby1and its analogues. Correlating data between the liposome and bacteria experiments revealed that membrane lysis was mainly responsible for the antibacterial functions. Altering the cationic guanidine moiety ofd‐Arg‐2/7 to a neutral amide, and the C7‐acyl group ofl‐Thr‐1 to the C2 or C11 counterpart decreased the antimicrobial activities four‐ or eight‐fold. More drastically, chemical mutation ofd‐Trp‐10 tod‐Ala‐10 totally abolished the bioactivities. These important findings led us to propose the biological roles of the side‐chain functionalities.