Semisynthetic Flavone-Derived Antimicrobials with Therapeutic Potential against Methicillin-Resistant Staphylococcus aureus (MRSA),Journal of Medicinal Chemistry

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Semisynthetic Flavone-Derived Antimicrobials with Therapeutic Potential against Methicillin-Resistant Staphylococcus aureus (MRSA)
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-07-07 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00380
Shuimu Lin _{1,

2,

3} , Jun-Jie Koh ₂ , Thet Tun Aung ₂ , Wan Ling Wendy Sin ₂ , Fanghui Lim ₂ , Lin Wang _{1,

3} , Rajamani Lakshminarayanan _{2,

4} , Lei Zhou _{2,

4} , Donald T. H. Tan _{2,

5} , Derong Cao ₆ , Roger W. Beuerman _{2,

4} , Li Ren _{1,

3} , Shouping Liu _{2,

4}

Affiliation

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.

中文翻译：

半合成的黄酮类抗生素具有抗甲氧西林金黄色葡萄球菌（MRSA）的治疗潜力

从天然icaritin设计了一系列新的基于半黄酮的模拟抗菌肽的小分子，以对抗耐药的革兰氏阳性细菌感染。含有两个精氨酸残基的化合物6对革兰氏阳性细菌（包括MRSA）表现出优异的抗菌活性，并且对哺乳动物细胞的毒性极低，因此与临床试验中的几种具有膜活性的抗生素相比，其选择性高达511以上。我们的数据首次表明，icaritin衍生物可有效杀死细菌。同时，这是第一项采用仿生策略来设计有效的基于黄酮的膜靶向抗菌剂的研究。6通过破坏细菌膜表现出快速的杀菌活性，可以规避细菌抗药性的发展。重要的是，6在由MRSA和金黄色葡萄球菌引起的角膜感染的小鼠模型中非常有效。

更新日期：2017-07-08

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