Antimicrobial activity and stability of protonectin with D‐amino acid substitutions
Antimicrobial activity and stability of protonectin with D‐amino acid substitutions
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DOI：
10.1002/psc.2989
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发表时间：
2017-03
影响因子：
2.1
通讯作者：
Shuai Qiu;Ranran Zhu;Yanyan Zhao;Xiaoping An;Fengjing Jia;Jinxiu Peng;Zelin Ma;Yuan-Yuan Zhu-Yuan-
中科院分区：
文献类型：
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作者：
Shuai Qiu;Ranran Zhu;Yanyan Zhao;Xiaoping An;Fengjing Jia;Jinxiu Peng;Zelin Ma;Yuan-Yuan Zhu-Yuan-
抗生素的滥用和过度使用导致了耐药菌和耐药真菌的出现，迫切需要新的抗菌药物。近年来，抗菌肽的研究引起了人们的广泛关注。然而，天然抗菌肽在生物系统中的低生理稳定性限制了其作为新型治疗药物的应用。在本研究中，我们通过用相应的D-氨基酸取代所有的氨基酸残基或阳离子赖氨酸残基来合成Protonectin的衍生物。质子蛋白的D-对映体（D-prt）和D-Lys-质子蛋白（D-Lys-prt）对细菌和真菌都表现出很强的抗菌活性。此外，D-prt对胰蛋白酶、胰凝乳蛋白酶和人血清显示出强稳定性，而D-Lys-prt仅对胰蛋白酶显示出强稳定性。圆二色性分析表明，D-Lys-prt在模拟膜的环境中仍保持典型的α-螺旋结构，而D-prt则表现为左手型α-螺旋结构。此外，碘化丙啶摄取测定和细菌和真菌杀灭实验表明，所有D-氨基酸取代或部分D-氨基酸取代类似物可破坏膜的完整性并导致细胞死亡。总之，这些结果表明，D‐prt和D‐Lys‐prt可能是治疗耐药细菌和真菌感染的有前景的候选抗生素。版权所有© 2017 European Peptide Society and John Wiley & Sons，Ltd.
The misuse and overuse of antibiotics result in the emergence of resistant bacteria and fungi, which make an urgent need of the new antimicrobial agents. Nowadays, antimicrobial peptides have attracted great attention of researchers. However, the low physiological stability in biological system limits the application of naturally occurring antimicrobial peptides as novel therapeutics. In the present study, we synthesized derivatives of protonectin by substituting all the amino acid residues or the cationic lysine residue with the corresponding D‐amino acids. Both the D‐enantiomer of protonectin (D‐prt) and D‐Lys‐protonectin (D‐Lys‐prt) exhibited strong antimicrobial activity against bacteria and fungi. Moreover, D‐prt showed strong stability against trypsin, chymotrypsin and the human serum, while D‐Lys‐prt only showed strong stability against trypsin. Circular dichroism analysis revealed that D‐Lys‐prt still kept typical α‐helical structure in the membrane mimicking environment, while D‐prt showed left hand α‐helical structure. In addition, propidium iodide uptake assay and bacteria and fungi killing experiments indicated that all D‐amino acid substitution or partially D‐amino acid substitution analogs could disrupt the integrity of membrane and lead the cell death. In summary, these findings suggested that D‐prt and D‐Lys‐prt might be promising candidate antibiotic agents for therapeutic application against resistant bacteria and fungi infection. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.