Structural optimization and antibacterial evaluation of rhodomyrtosone B analogues against MRSA strains
Structural optimization and antibacterial evaluation of rhodomyrtosone B analogues against MRSA strains
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红桃醛酮 B 类似物对 MRSA 菌株的结构优化及抗菌评价
DOI：
10.1039/c8md00257f
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Qiu Shengxiang
中科院分区：
文献类型：
--
作者：
Zhao Liyun;Liu Hongxin;Huo Luqiong;Wang Miaomiao;Yang Bao;Zhang Weimin;Xu Zhifang;Tan Haibo;Qiu Shengxiang
耐甲氧西林金黄色葡萄球菌（MRSA）感染是众所周知的重大全球卫生挑战。本研究合成了天然抗生素rhodomyrtosone B （RDSB）的22个同源物，目的是通过修饰其悬垂的酰基片段特异性地增强其结构多样性。对不同MRSA菌株的构效关系研究表明，间苯三酚支架中合适的疏水性酰基尾部是其抗菌活性的先决条件。值得注意的是，RDSB类似物11k被确定为一种有前景的先导化合物，对一组与医院死亡率相关的MRSA菌株具有显著的体外和体内抗菌活性。此外，化合物11k还具有其他强大的优势，包括抗菌谱的宽度、杀菌作用的速度和优异的膜选择性。化合物11k在生物物理和形态学水平上的作用模式研究表明，11k通过膜超极化导致细胞裂解和膜破坏来发挥其MRSA杀菌作用。总之，上述结果表明，新型修饰的RDSB类似物11k作为治疗MRSA感染的有希望的候选物值得进一步探索。
Methicillin-resistant Staphylococcus aureus (MRSA) infections are well-known as a significant global health challenge. In this study, twenty-two congeners of the natural antibiotic rhodomyrtosone B (RDSB) were synthesized with the aim of specifically enhancing the structural diversity through modifying the pendant acyl moiety. The structure–activity relationship study against various MRSA strains revealed that a suitable hydrophobic acyl tail in the phloroglucinol scaffold is a prerequisite for antibacterial activity. Notably, RDSB analogue 11k was identified as a promising lead compound with significant in vitro and in vivo antibacterial activities against a panel of hospital mortality-relevant MRSA strains. Moreover, compound 11k possessed other potent advantages, including breadth of the antibacterial spectrum, rapidity of bactericidal action, and excellent membrane selectivity. The mode of action study of compound 11k at the biophysical and morphology levels disclosed that 11k exerted its MRSA bactericidal action by membrane superpolarization resulting in cell lysis and membrane disruption. Collectively, the presented results indicate that the novel modified RDSB analogue 11k warrants further exploration as a promising candidate for the treatment of MRSA infections.