Acid-Activated Antimicrobial Random Copolymers: A Mechanism-Guided Design of Antimicrobial Peptide Mimics
Acid-Activated Antimicrobial Random Copolymers: A Mechanism-Guided Design of Antimicrobial Peptide Mimics
复制标题
酸激活抗菌无规共聚物：抗菌肽模拟物的机制引导设计
DOI：
10.1021/ma400484b
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发表时间：
2013-05-28
期刊：
影响因子：
5.5
通讯作者：
Yang, Lihua
中科院分区：
文献类型：
--
作者：
Jiang, Yunjiang;Yang, Xin;Yang, Lihua
如何减少抗菌药物给药期间的脱靶不良反应仍然是一个持续的挑战。我们展示了酸活化抗菌肽模拟物（aSMAMP）的机制指导设计，其具有由酸性pH触发的抗菌活性，这是与许多感染状况相关的因素。已知膜活性抗菌剂的阳离子性促进活性。通过加强一个额外的pH响应单体的膜活性抗菌无规共聚物，我们得到aSMAMP，是净中性在生理pH值，但净阳离子在酸性pH值。平板杀伤试验表明，大肠杆菌细胞在pH值5.0，而不是那些在pH值7.4时，易受这种aSMAMP，而相反的是真实的挑战时，与传统的代谢抗生素。aSMAMP和在两种pH条件下均为阳离子的一种同系物之间的比较表明，aSMAMP的酸触发的抗菌活性可能归因于其pH可调的净阳离子性。在正常血液pH下，这些aSMAMP表现出对人红细胞的溶血毒性大大降低。总之，这样的aSMAMP表明，通过pH打开或关闭膜活性抗微生物剂的阳离子基序提供了一种可行的方法，该方法可以实现具有由与许多感染状况相关的酸性pH触发的活性的“智能”抗微生物剂，这可能在抗微生物剂施用期间减少对微生物群和宿主细胞的脱靶不良作用方面具有意义。
How to reduce the off-target adverse effects during antimicrobial administration remains an ongoing challenge. We show a mechanism-guided design of acid-activated antimicrobial peptide mimics (aSMAMPs) that have antibacterial activity triggered by acidic pH, a factor associated with many infected conditions. The cationicity of membrane-active antimicrobials is known to facilitate activity. By reinforcing a membrane-active antimicrobial random copolymer with an extra pH responsive monomer, we obtain aSMAMP that is net neutral at physiological pH but net cationic at acidic pH. Plate killing assays indicate that Escherichia coli cells at pH 5.0 rather than those at pH 7.4 are susceptible to such aSMAMPs, whereas the opposite is true when challenged with conventional metabolic antibiotics. Comparison between the aSMAMPs and one homologue that is cationic at both pH conditions suggests that the acid-triggered antibacterial activity of aSMAMPs may be attributed to their pH-tunable net cationicity. At normal blood pH, these aSMAMPs demonstrate greatly diminished hemolytic toxicity against human erythrocytes. Taken together, such aSMAMPs show that switching on-or-off the cationic motif of a membrane-active antimicrobial via pH offers a feasible approach toward "smart" antimicrobials with activity triggered by acidic pH associated with many infected conditions, which may have implications in reducing the off-target adverse effects on both microbiota and host cells during antimicrobial administration.