Halogenation as a tool to tune antimicrobial activity of peptoids
Halogenation as a tool to tune antimicrobial activity of peptoids
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DOI：
10.1038/s41598-020-71771-8
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发表时间：
2020-09-09
影响因子：
4.6
通讯作者：
Jenssen, Havard
中科院分区：
文献类型：
--
作者：
Molchanova, Natalia;Nielsen, Josefine Eilso;Jenssen, Havard
抗菌肽作为一类潜在的新型抗生素，已引起人们极大的兴趣。然而，它们的治疗潜力是有限的，部分原因是对酶降解和低生物利用度的敏感性。类肽（N-取代甘氨酸的低聚物）表现出比相应肽更好的蛋白水解稳定性和生物利用度，同时在许多情况下保留抗菌活性。在这项研究中，我们合成了36个含有氟，氯，溴和碘原子的肽库，这些肽的长度和苯环4位卤素取代的水平不同。由于我们观察到无活性模型类肽的卤化与其增加的抗微生物活性之间存在明确的相关性，我们设计了已知类肽及其较短对应物的氯化和溴化类似物。短溴化类似物对S.对金黄色葡萄球菌（E. aureus）的敏感性为16 ~ 64倍。大肠杆菌和铜绿假单胞菌，同时细胞毒性降低。卤素的生物效应似乎与化合物的相对疏水性和自组装特性有关。通过小角X射线散射（SAXS），我们已经证明了自组装结构是如何依赖于卤素的大小，取代度和类肽的长度，并将这些功能与它们的活性。
Antimicrobial peptides have attracted considerable interest as potential new class of antibiotics against multi-drug resistant bacteria. However, their therapeutic potential is limited, in part due to susceptibility towards enzymatic degradation and low bioavailability. Peptoids (oligomers of N-substituted glycines) demonstrate proteolytic stability and better bioavailability than corresponding peptides while in many cases retaining antibacterial activity. In this study, we synthesized a library of 36 peptoids containing fluorine, chlorine, bromine and iodine atoms, which vary by length and level of halogen substitution in position 4 of the phenyl rings. As we observed a clear correlation between halogenation of an inactive model peptoid and its increased antimicrobial activity, we designed chlorinated and brominated analogues of a known peptoid and its shorter counterpart. Short brominated analogues displayed up to 32-fold increase of the activity against S. aureus and 16- to 64-fold against E. coli and P. aeruginosa alongside reduced cytotoxicity. The biological effect of halogens seems to be linked to the relative hydrophobicity and self-assembly properties of the compounds. By small angle X-ray scattering (SAXS) we have demontrated how the self-assembled structures are dependent on the size of the halogen, degree of substitution and length of the peptoid, and correlated these features to their activity.