Lin Shuimu, Koh Jun-Jie, Aung Thet Tun, Sin Wan Ling Wendy, Lim Fanghui, Wang Lin, Lakshminarayanan Rajamani, Zhou Lei, Tan Donald T H, Cao Derong, Beuerman Roger W, Ren Li, Liu Shouping
School of Materials Science and Engineering, South China University of Technology , Guangzhou 510641, China.
Singapore Eye Research Institute , The Academia, 20 College Road, Discovery Tower Level 6, 169856 Singapore, Singapore.
J Med Chem. 2017 Jul 27;60(14):6152-6165. doi: 10.1021/acs.jmedchem.7b00380. Epub 2017 Jul 7.
A new series of semisynthetic flavone-based small molecules mimicking antimicrobial peptides has been designed from natural icaritin to combat drug-resistant Gram-positive bacterial infections. Compound 6 containing two arginine residues exhibited excellent antibacterial activity against Gram-positive bacteria, including MRSA, and very low toxicity to mammalian cells, resulting in a high selectivity of more than 511, comparable to that of several membrane-active antibiotics in clinical trials. Our data show for the first time that icaritin derivatives effectively kill bacteria. Meanwhile, this is the first study deploying a biomimicking strategy to design potent flavone-based membrane targeting antimicrobials. 6 showed rapid bactericidal activity by disrupting the bacterial membrane and can circumvent the development of bacterial resistance. Importantly, 6 was highly efficacious in a mouse model of corneal infection caused by MRSA and Staphylococcus aureus.
从天然淫羊藿素设计了一系列新的模仿抗菌肽的半合成黄酮类小分子，以对抗耐药物革兰氏阳性菌感染。含有两个精氨酸残基的化合物6对包括耐甲氧西林金黄色葡萄球菌（MRSA）在内的革兰氏阳性菌表现出优异的抗菌活性，对哺乳动物细胞的毒性极低，产生了超过511的高选择性，与几种临床试验中的膜活性抗生素相当。我们的数据首次表明淫羊藿素衍生物能有效杀死细菌。同时，这是首次采用仿生策略设计强效的基于黄酮的膜靶向抗菌剂的研究。化合物6通过破坏细菌膜表现出快速杀菌活性，并且可以规避细菌耐药性的产生。重要的是，化合物6在由MRSA和金黄色葡萄球菌引起的角膜感染小鼠模型中具有高效性。
