Structure-activity relationships and optimization of acyclic acylphloroglucinol analogues as novel antimicrobial agents
Structure-activity relationships and optimization of acyclic acylphloroglucinol analogues as novel antimicrobial agents
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无环酰基间苯三酚类似物作为新型抗菌剂的构效关系及优化
DOI：
10.1016/j.ejmech.2016.09.054
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发表时间：
2017
影响因子：
6.7
通讯作者：
Qiu Shengxiang
中科院分区：
文献类型：
--
作者：
Tan Haibo;Liu Hongxin;Zhao Liyun;Yuan Yao;Li Bailin;Jiang Yueming;Gong Liang;Qiu Shengxiang
耐甲氧西林金黄色葡萄球菌（MRSA）对现有抗生素具有耐药性，因此发病率和死亡率高，严重威胁着全球公共卫生。本研究合成了21个具有不同侧链的酰基间苯三酚同系物。对MRSA菌株的抗菌筛选表明，酰基部分剪裁是抗菌活性的先决条件。此外，亲脂性，而不是疏水酰基尾的大小主导活性效力的变化。化合物11 j被鉴定为用于产生新的抗MRSA药物开发的有希望的先导物。它是通过根据效力、抗菌谱的宽度、杀菌作用的速率以及膜选择性优化侧链长度而发现的。化合物11 j对MRSA菌株（JCSC 2172）具有较强的体外抗菌活性，其MIC比万古霉素低3-4个数量级。化合物11 j在生物物理学和形态学水平上的初步作用模式研究揭示了其抗MRSA活性的机制包括膜去极化，以及在较小程度上的膜破坏和细胞裂解。
Methicillin-resistantStaphylococcus aureus(MRSA) poses a serious threat to global public health, because it exhibits resistance to existing antibiotics and therefore high rates of morbidity and mortality. In this study, twenty-one natural product-based acylphloroglucinol congeners were synthesized, which possessed different side chains. Antibacterial screening against MRSA strains revealed that acyl moiety tailoring is a prerequisite for the antibacterial activity. Moreover, the lipophilicity, rather than the magnitude of the hydrophobic acyl tail dominates variability in activity potency. Compound11jwas identified as a promising lead for the generation of new anti-MRSA drug development. It was discovered by optimization of the side chain length in light of the potency, the breadth of the antibacterial spectrum, the rate of bactericidal action, as well as the membrane selectivity. Compound11jexerted profoundin vitroantibacterial activity against the MRSA strain (JCSC 2172), and its MIC was 3-4 orders of magnitude lower than that of vancomycin. A preliminary mode of action study of compound11jat the biophysical and morphology levels disclosed that the mechanism underlying its anti-MRSA activity included membrane depolarization and, to a lesser extent, membrane disruption and cell lysis.