Surprising alteration of antibacterial activity of 5"-modified neomycin against resistant bacteria.
Surprising alteration of antibacterial activity of 5"-modified neomycin against resistant bacteria.
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DOI：
10.1021/jm800997s
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发表时间：
2008-12-11
影响因子：
7.3
通讯作者：
Chang CW
中科院分区：
文献类型：
--
作者：
Zhang J;Chiang FI;Wu L;Czyryca PG;Li D;Chang CW
本文报道了一种简便的5″位修饰新霉素B衍生物的合成方法。研究了不同氨基糖苷类修饰酶（AME’s）对氨基糖苷类耐药菌的构效关系（SAR）。酶和分子建模研究表明，尽管观察到几种衍生物显示出比母体新霉素增强的抗菌活性，但AME的极好的底物混杂性允许抗性细菌科普不同的结构修饰。令人惊讶的是，当测试合成的新霉素衍生物对抗其他人类病原体时，两种先导物表现出对抗耐甲氧西林金黄色葡萄球菌（MRSA）和耐万古霉素肠球菌（VRE）的突出活性，已知这两种耐甲氧西林金黄色葡萄球菌（MRSA）和耐万古霉素肠球菌（VRE）对临床使用的氨基糖苷类产生高水平的抗性。这些发现对于开发针对耐药细菌的新氨基糖苷类抗生素非常有用。我们的研究结果还表明，新的生物活性和抗菌活性可以通过化学修饰的老药物。
A facile synthetic protocol for the production of neomycin B derivatives with various modifications at the 5″ position has been developed. Structural activity relationship (SAR) against aminoglycoside resistant bacteria equipped with various aminoglycoside-modifying enzymes (AME's) was investigated. Enzymatic and molecular modeling studies reveal that the superb substrate promiscuity of AME's allows the resistant bacteria to cope with diverse structural modifications despite the observation that several derivatives show enhanced antibacterial activity than the parent neomycin. Surprisingly, when testing synthetic neomycin derivatives against other human pathogens, two leads exhibit prominent activity against both Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) that are known to exert high level of resistance against clinically used aminoglycosides. These findings can be extremely useful in developing new aminoglycoside antibiotics against resistant bacteria. Our result also suggests that new biological and antimicrobial activities can be obtained by chemical modifications of old drugs.
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