An alternatingly amphiphilic, resistance-resistant antimicrobial oligoguanidine with dual mechanisms of action
An alternatingly amphiphilic, resistance-resistant antimicrobial oligoguanidine with dual mechanisms of action
复制标题
具有双重作用机制的交替两亲性、耐药性抗菌寡胍
DOI：
10.1016/j.biomaterials.2021.120858
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发表时间：
2021-05-24
期刊：
影响因子：
14
通讯作者：
Bai, Yugang
中科院分区：
文献类型：
--
作者：
Chen, Zhiyong;Zhou, Cailing;Bai, Yugang
由多重耐药（MDR）细菌引起的感染数量不断增加，预示着一个新的全球挑战。抗菌肽及其模拟物是目前正在开发的一种新型抗菌药物，由于其膜破坏作用机制导致耐药率低，对耐多药菌株的有效性低，因此具有很高的应用潜力。然而，大多数报道的AMP和AMP模拟物具有表面两亲性结构，这可能导致不期望的自聚集和非特异性结合，以及对哺乳动物细胞的细胞毒性增加，所有这些都对其应用造成了显著限制。在这里，我们报告了一个寡聚体的大小短AMP，与疏水性碳链和阳离子基团放置在其主链上，给一个交替的两亲性结构，带来更好的哺乳动物和细菌细胞膜之间的选择性。此外，寡聚体对DNA具有亲和力，因此它可以利用位于脆弱类核中的细菌DNA作为第二药物靶标。得益于这些设计，该寡聚体显示出更高的治疗指数和与其他抗生素的协同作用，同时可以保持其低的耐药产生率和对多重耐药菌株的有效性。我们证明，这种交替的两亲性，DNA结合寡聚体不仅耐药，但也能够选择性地消除细菌在哺乳动物细胞的存在。重要的是，该寡聚体表现出良好的体内活性：它清除秀丽隐杆线虫上的所有细菌而不引起明显的毒性，并且在小鼠切除伤口模型研究中显著提高了具有严重感染伤口的小鼠的存活率。
The increasing number of infections caused by multi-drug resistance (MDR) bacteria is an omen of a new global challenge. As one of the countermeasures under development, antimicrobial peptides (AMPs) and AMP mimics have emerged as a new family of antimicrobial agents with high potential, due to their low resistance generation rate and effectiveness against MDR bacterial strains resulted from their membrane-disrupting mechanism of action. However, most reported AMPs and AMP mimics have facially amphiphilic structures, which may lead to undesired self-aggregation and non-specific binding, as well as increased cytotoxicity toward mammalian cells, all of which put significant limits on their applications. Here, we report an oligomer with the size of short AMPs, with both hydrophobic carbon chain and cationic groups placed on its backbone, giving an alternatingly amphiphilic structure that brings better selectivity between mammalian and bacterial cell membranes. In addition, the oligomer shows affinity toward DNA, thus it can utilize bacterial DNA located in the vulnerable nucleoid as the second drug target. Benefiting from these designs, the oligomer shows higher therapeutic index and synergistic effect with other antibiotics, while its low resistance generation rate and effectiveness on multidrug resistant bacterial strains can be maintained. We demonstrate that this alternatingly amphiphilic, DNAbinding oligomer is not only resistance-resistant, but is also able to selectively eliminate bacteria at the presence of mammalian cells. Importantly, the oligomer exhibits good in vivo activity: it cleans all bacteria on Caenorhabditis elegans without causing apparent toxicity, and significantly improves the survival rate of mice with severely infected wounds in a mice excision wound model study.