Degradable antimicrobial polycarbonates with unexpected activity and selectivity for treating multidrug-resistant Klebsiella pneumoniae lung infection in mice.
Degradable antimicrobial polycarbonates with unexpected activity and selectivity for treating multidrug-resistant Klebsiella pneumoniae lung infection in mice.
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DOI：
10.1016/j.actbio.2019.05.057
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发表时间：
2019-05
影响因子：
9.7
通讯作者：
Chuan Yang;Weiyang Lou;Guansheng Zhong;Ashlynn L. Z. Lee;Jiayu Leong;Willy Chin;Bisha Ding;C. Bao;J. Tan;Qinqin Pu;Shujun Gao;Liang Xu;L. Hsu;Min Wu;J. Hedrick;W. Fan;Yi Yan Yang
中科院分区：
文献类型：
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作者：
Chuan Yang;Weiyang Lou;Guansheng Zhong;Ashlynn L. Z. Lee;Jiayu Leong;Willy Chin;Bisha Ding;C. Bao;J. Tan;Qinqin Pu;Shujun Gao;Liang Xu;L. Hsu;Min Wu;J. Hedrick;W. Fan;Yi Yan Yang
多重耐药 (MDR) 肺炎克雷伯菌是世界各地医疗保健相关感染的主要原因，伴随着高发病率和死亡率。由于耐药性不断升级，能够治疗 MDRK 肺炎感染（包括肺部感染）的抗生素效力逐渐降低，这为开发针对 MDRK 的候选药物提供了动力。肺炎杆菌。我们最近报道了可降解的广谱抗菌胍基功能化聚碳酸酯，具有独特的抗菌机制——膜易位，随后胞质材料沉淀。这些聚合物对细菌表现出高效能，且毒性可忽略不计。奎尼鎓基团和聚合物主链之间具有乙基间隔基的聚合物（pEt_20）显示出优异的治疗 MDRK 的体内功效。肺炎支原体引起小鼠腹膜炎。在这项研究中，优化了聚合物的结构，用于治疗 MDRK 肺炎杆菌肺部感染。具体而言，评估了含有相同数量胍基团但链长较短的胍官能化聚碳酸酯和含有硫脲部分作为侧挂阳离子基团的结构类似物的体外抗菌活性和选择性。根据 25 个临床分离的 K 评估具有最佳组成和不同疏水性的聚合物。肺炎菌株的抗菌活性和杀伤动力学。结果表明，该聚合物比临床使用的抗生素更有效地杀死细菌，并且重复使用该聚合物不会导致K菌产生耐药性。肺炎。特别是，带有丁基间隔基的聚合物（pBut_20）在高浓度下自组装成胶束，其中疏水成分被屏蔽在胶束核心中，防止与哺乳动物细胞相互作用。疏水性的细微变化增加了抗菌活性，同时降低了体内毒性。体内功效研究表明pBut_20减轻了K。肺炎肺部感染不会对主要器官造成损害。总而言之，pBut_20有望用于治疗体内MDRK肺炎克雷伯菌肺部感染。意义声明多重耐药（MDR）肺炎克雷伯菌是医疗保健相关感染的主要原因，伴随着高发病率和死亡率。由于耐药率上升，能够治疗MDRK肺炎感染（包括肺部感染）的抗生素逐渐减少，这为开发候选药物提供了动力。在这项研究中，我们报告了一种可降解的胍基功能化聚碳酸酯，具有意想不到的抗菌活性和对 MDRK 肺炎杆菌的选择性。聚合物疏水性的微妙变化增加了抗菌活性，同时降低了由于高浓度自组装而产生的体内毒性。具有最佳成分的聚合物可减轻肺炎克雷伯菌肺部感染，而不会对主要器官造成损害。该聚合物有望用于治疗体内MDRK肺炎杆菌肺部感染。
Multidrug resistant (MDR)Klebsiella pneumoniaeis a major cause of healthcare-associated infections around the world, with attendant high rates of morbidity and mortality. Progressive reduction in potency of antibiotics capable of treating MDRK.pneumoniaeinfections – including lung infection – as a consequence of escalating drug resistance provides the motivation to develop drug candidates targeting MDRK. pneumoniae. We recently reported degradable broad-spectrum antimicrobial guanidinium-functionalized polycarbonates with unique antimicrobial mechanism – membrane translocation followed by precipitation of cytosolic materials. These polymers exhibited high potency against bacteria with negligible toxicity. The polymer with ethyl spacer between the quanidinium group and the polymer backbone (pEt_20) showed excellentin vivoefficacy for treating MDRK. pneumoniae-caused peritonitis in mice. In this study, the structures of the polymers were optimized for the treatment of MDRKlebsiella pneumoniaelung infection. Specifically,in vitroantimicrobial activity and selectivity of guanidinium-functionalized polycarbonates containing the same number of guanidinium groups but of a shorter chain length and a structural analogue containing a thiouronium moiety as the pendent cationic group were evaluated. The polymers with optimal compositions and varying hydrophobicity were assessed against 25 clinically isolatedK. pneumoniastrains for antimicrobial activity and killing kinetics. The results showed that the polymers killed the bacteria more efficiently than clinically used antibiotics, and repeated use of the polymers did not cause drug resistance inK. pneumonia. Particularly, the polymer with butyl spacer (pBut_20) self-assembled into micelles at high concentrations, where the hydrophobic component was shielded in the micellar core, preventing interacting with mammalian cells. A subtle change in the hydrophobicity increased the antimicrobial activity while reducingin vivotoxicity. Thein vivoefficacy studies showed that pBut_20 alleviatedK. pneumonialung infection without inducing damage to major organs. Taken together, pBut_20 is promising for treating MDRKlebsiella pneumoniaelung infectionin vivo.Statement of SignificanceMultidrug resistant (MDR)Klebsiella pneumoniaeis a major cause of healthcare-associated infections, with attendant high rates of morbidity and mortality. The progressive reduction in antibiotics capable of treating MDRK.pneumoniaeinfections – including lung infection – as a consequence of escalating drug resistance rates provides the motivation to develop drug candidates. In this study, we report a degradable guanidinium-functionalized polycarbonate with unexpected antimicrobial activity and selectivity towards MDRKlebsiella pneumoniae. A subtle change in polymer hydrophobicity increases antimicrobial activity while reducingin vivotoxicity due to self-assembly at high concentrations. The polymer with optimal composition alleviatesKlebsiella pneumonialung infection without inducing damage to major organs. The polymer is promising for treating MDRKlebsiella pneumoniaelung infectionin vivo.