Department of Pharmacy, Jaypee University of Information Technology, Solan, 173234, India.
Chem Biol Drug Des. 2013 Nov;82(5):557-66. doi: 10.1111/cbdd.12182. Epub 2013 Aug 9.
We describe the design and synthesis of a new series of non-natural short cationic lipopeptides (MW = 700) as antimicrobial agents. All of the synthesized lipopeptides were tested against a range of microbes such as Gram-positive, Gram-negative bacteria, fungi including methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE). By systematic study of design template, we found that three ornithine residues conjugated with myristic acid are minimum requirement for a compound to be an antimicrobial agent. The most potent lipopeptide LP16 possesses broad-spectrum antimicrobial activity and has MICs in the range of 1.5-6.25 μg/mL against Escherichia coli, S. aureus, Pseudomonas aeruginosa, Bacillus subtilis, and MRSE. All lipopeptides showed high selectivity toward microbial strains as compared to human red blood cells (HC50 > 250 μg/mL). Moreover, most potent lipopeptides (LP16 and LP23) did not induce drug resistance in S. aureus even after 15 rounds of passaging. In addition, a representative lipopeptide (LP16) showed tryptic stability for 24 h. These results suggest the potential of short cationic lipopeptides to boost the discovery of future antimicrobial therapeutics.
我们设计并合成了一系列新的非天然短阳离子脂肽（MW=700）作为抗菌剂。所有合成的脂肽都针对一系列微生物进行了测试，如革兰氏阳性菌、革兰氏阴性菌、真菌，包括耐甲氧西林金黄色葡萄球菌（MRSA）和耐甲氧西林表皮葡萄球菌（MRSE）。通过对设计模板的系统研究，我们发现三个与豆蔻酸偶联的鸟氨酸残基是化合物成为抗菌剂的最低要求。最有效的脂肽 LP16 具有广谱抗菌活性，对大肠杆菌、金黄色葡萄球菌、铜绿假单胞菌、枯草芽孢杆菌和 MRSE 的 MIC 范围在 1.5-6.25μg/mL 之间。与人类红细胞（HC50>250μg/mL）相比，所有脂肽对微生物菌株都表现出很高的选择性。此外，即使经过 15 轮传代，最强效的脂肽（LP16 和 LP23）也不会诱导金黄色葡萄球菌产生耐药性。此外，代表性脂肽（LP16）在 24 小时内保持胰蛋白酶稳定性。这些结果表明，短阳离子脂肽具有发现未来抗菌治疗药物的潜力。
