Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2.
Carbohydr Res. 2011 Apr 1;346(5):560-8. doi: 10.1016/j.carres.2011.01.015. Epub 2011 Jan 21.
Amphiphilic lysine-ligated neomycin B building blocks were prepared by reductive amination of a protected C5″-modified neomycin B-based aldehyde and side chain-unprotected lysine or lysine-containing peptides. It was demonstrated that a suitably protected lysine-ligated neomycin B conjugate (NeoK) serves as a building block for peptide synthesis, enabling incorporation of aminoglycoside binding sites into peptides. Antibacterial testing of three amphiphilic lysine-ligated neomycin B conjugates against a representative panel of Gram-positive and Gram-negative strains demonstrates that C5″-modified neomycin-lysine conjugate retains antibacterial activity. However, in most cases the lysine-ligated neomycin B analogs display reduced potency against Gram-positive strains when compared to unmodified neomycin B or unligated peptide. An exception is MRSA where an eightfold enhancement was observed. When compared to unmodified neomycin B, the prepared lysine-neomycin conjugates exhibited a 4-8-fold enhanced Gram-negative activity against Pseudomonas aeruginosa and up to 12-fold enhanced activity was observed when compared to unligated reference peptides.
通过对保护的 C5″-修饰的新霉素 B 醛基与侧链未保护的赖氨酸或含赖氨酸的肽进行还原胺化，制备了双亲性赖氨酸连接的新霉素 B 砌块。研究表明，适当保护的赖氨酸连接的新霉素 B 缀合物（NeoK）可用作肽合成的构建块，从而能够将氨基糖苷结合位点掺入肽中。对三种双亲性赖氨酸连接的新霉素 B 缀合物针对代表性的革兰氏阳性和革兰氏阴性菌株的抗菌测试表明，C5″-修饰的新霉素-赖氨酸缀合物保留了抗菌活性。但是，在大多数情况下，与未修饰的新霉素 B 或未连接的肽相比，赖氨酸连接的新霉素 B 类似物对革兰氏阳性菌株的效力降低。MRSA 是一个例外，观察到了八倍的增强。与未修饰的新霉素 B 相比，所制备的赖氨酸新霉素缀合物对铜绿假单胞菌的革兰氏阴性活性增强了 4-8 倍，与未连接的参考肽相比，活性增强了 12 倍。
