Synthesis and antimicrobial activity against Pseudomonas aeruginosa of macrocyclic β-hairpin peptidomimetic antibiotics containing N-methylated amino acids
Synthesis and antimicrobial activity against Pseudomonas aeruginosa of macrocyclic β-hairpin peptidomimetic antibiotics containing N-methylated amino acids
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DOI：
10.1016/j.bmc.2016.05.027
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发表时间：
2016-12-15
影响因子：
3.5
通讯作者：
Robinson, John A.
中科院分区：
文献类型：
--
作者：
Vetterli, Stefan U.;Moehle, Kerstin;Robinson, John A.
革兰氏阴性菌中的抗菌素耐药性是一个日益严重的问题，由于缺乏针对这些微生物的新抗生素而加剧。一个新的大环β-发夹形肽模拟物家族最近被证明特异性地对抗假单胞菌属。通过一种新的作用机制，靶向外膜蛋白LptD，其在外膜生物发生期间介导脂多糖转运至细胞表面。在这里，我们探索的模式，结合这些β发夹肽模拟物的LptD在铜绿假单胞菌，通过检查后的抗微生物活性的影响，N-甲基化的个别肽键。环肽的N-甲基扫描显示，β-发夹结构两侧非氢键位置的残基可能介导与靶LptD的氢键相互作用。通过NMR光谱进行的结构分析进一步强化了肽模拟物的折叠β-发夹结构对于结合靶LptD至关重要的结论。最后，已经鉴定了具有有效活性的新的NMe类似物，这为优化该抗菌肽家族开辟了新的途径。(C)2016爱思唯尔有限公司版权所有。
Antimicrobial resistance among Gram-negative bacteria is a growing problem, fueled by the paucity of new antibiotics that target these microorganisms. One novel family of macrocyclic beta-hairpin-shaped peptidomimetics was recently shown to act specifically against Pseudomonas spp. by a novel mechanism of action, targeting the outer membrane protein LptD, which mediates lipopolysaccharide transport to the cell surface during outer membrane biogenesis. Here we explore the mode of binding of one of these (3 hairpin peptidomimetics to LptD in Pseudomonas aeruginosa, by examining the effects on antimicrobial activity following N-methylation of individual peptide bonds. An N-methyl scan of the cyclic peptide revealed that residues on both sides of the beta-hairpin structure at a non-hydrogen bonding position likely mediate hydrogen-bonding interactions with the target LptD. Structural analyses by NMR spectroscopy further reinforce the conclusion that the folded beta-hairpin structure of the peptidomimetic is critical for binding to the target LptD. Finally, new NMe analogues with potent activity have been identified, which opens new avenues for optimization in this family of antimicrobial peptides. (C) 2016 Elsevier Ltd. All rights reserved.