Key Laboratory of Superlight Materials & Surface Technology, Ministry of Education, Institute of Advanced Marine Materials, College of Materials Science and Chemical Engineering, Harbin Engineering University, Harbin 150001, China.
College of Pharmacy, Qiqihar Medical University, Qiqihar 161000, China.
Bioorg Chem. 2021 Jan;106:104506. doi: 10.1016/j.bioorg.2020.104506. Epub 2020 Nov 24.
Thirteen cationic peptidomimetics derived from amino acids bearing an alkyl or ethynylphenyl moiety that mimic the structure of cationic antibacterial peptides were designed and synthesized using a simple coupling reaction of an amino acid with a substituted amine. Antibacterial activities of the resulting peptidomimetics against drug-sensitive bacteria, such as Gram-positive Staphylococcus aureus (S. aureus) and Bacillus subtilis, Gram-negative Escherichia coli (E. coli) and Salmonella enterica, and a drug-resistant bacterium, methicillin-resistant S. aureus (MRSA), were systematically evaluated. Most peptidomimetics show significant broad-spectrum antibacterial activity. A-L-Iso-C (isoleucine derivative bearing a dodecyl moiety) show MICs of 2.5 μg/mL against S. aureus and 4 μg/mL against MRSA and A-L-Val-C (valine derivative bearing a dodecyl moiety) show MICs of 1.67 μg/mL against E. coli and 8.3 μg/mL against MRSA. A-L-Val-C showed low cytotoxicity toward L929 cells in comparison with SGC 7901 cells, indicating tumor-directed killing by peptidomimetics while avoiding toxicity to normal cells. The influences of type of amino acid and substituent, length of substituent, and stereochemistry of amino acids on antibacterial activity and cytotoxicity of peptidomimetics were systematically investigated. The results indicate that this series of cationic peptidomimetics derived from amino acids display antitumor activity and may be useful for treatment of bacterial infections.
设计并合成了 13 种源于带有烷基或炔基苯基部分的氨基酸的阳离子肽模拟物，这些模拟物模拟了阳离子抗菌肽的结构。使用氨基酸与取代胺的简单偶联反应来合成这些肽模拟物。系统评估了所得肽模拟物对敏感细菌（如革兰氏阳性的金黄色葡萄球菌（S. aureus）和枯草芽孢杆菌，革兰氏阴性的大肠杆菌（E. coli）和沙门氏菌，以及耐药菌耐甲氧西林金黄色葡萄球菌（MRSA）的抗菌活性。大多数肽模拟物显示出显著的广谱抗菌活性。A-L-Iso-C（带有十二烷基部分的异亮氨酸衍生物）对 S. aureus 的 MIC 为 2.5μg/mL，对 MRSA 的 MIC 为 4μg/mL；A-L-Val-C（带有十二烷基部分的缬氨酸衍生物）对 E. coli 的 MIC 为 1.67μg/mL，对 MRSA 的 MIC 为 8.3μg/mL。与 SGC 7901 细胞相比，A-L-Val-C 对 L929 细胞的细胞毒性较低，表明肽模拟物具有肿瘤定向杀伤作用，同时避免了对正常细胞的毒性。系统研究了氨基酸和取代基的类型、取代基的长度以及氨基酸的立体化学对肽模拟物的抗菌活性和细胞毒性的影响。结果表明，该系列源于氨基酸的阳离子肽模拟物具有抗肿瘤活性，可能有助于治疗细菌感染。
