Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B.
Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B.
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DOI：
10.1021/acs.jmedchem.5b01593
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发表时间：
2016-02-11
影响因子：
7.3
通讯作者：
Cooper MA
中科院分区：
文献类型：
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作者：
Gallardo-Godoy A;Muldoon C;Becker B;Elliott AG;Lash LH;Huang JX;Butler MS;Pelingon R;Kavanagh AM;Ramu S;Phetsang W;Blaskovich MA;Cooper MA
多粘菌素脂十肽粘杆菌素和多粘菌素B已成为由高度耐药的革兰氏阴性菌引起的感染的最后疗法。不幸的是，它们的效用受到显著的肾毒性和多粘菌素耐药菌株的影响。我们已经进行了系统的活性-毒性调查，通过改变9个多粘菌素氨基酸游离侧链中的8个，使用一种新的固相合成路线制备30多个类似物。针对一组革兰氏阴性细菌测试化合物，并针对体外细胞毒性进行反筛选。有前途的化合物进行了额外的测试，对原代肾细胞分离自人类肾脏，以更好地预测其肾毒性的潜力。许多新化合物与多粘菌素B相比具有同等或更好的抗菌效力，其中一些化合物对哺乳动物HepG 2细胞和人原代肾细胞的毒性低于多粘菌素B和粘菌素。这些最初的结构-活性和结构-毒性研究为进一步改进多粘菌素类抗生素奠定了基础。
The polymyxin lipodecapeptides colistin and polymyxin B have become last resort therapies for infections caused by highly drug-resistant Gram-negative bacteria. Unfortunately, their utility is compromised by significant nephrotoxicity and polymyxin-resistant bacterial strains. We have conducted a systematic activity–toxicity investigation by varying eight of the nine polymyxin amino acid free side chains, preparing over 30 analogues using a novel solid-phase synthetic route. Compounds were tested against a panel of Gram-negative bacteria and counter-screened for in vitro cell toxicity. Promising compounds underwent additional testing against primary kidney cells isolated from human kidneys to better predict their nephrotoxic potential. Many of the new compounds possessed equal or better antimicrobial potency compared to polymyxin B, and some were less toxic than polymyxin B and colistin against mammalian HepG2 cells and human primary kidney cells. These initial structure–activity and structure–toxicity studies set the stage for further improvements to the polymyxin class of antibiotics.