Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
Department of Food Science, Faculty of Science, University of Copenhagen, Rolighedsvej 26, 1958, Frederiksberg, Denmark.
Sci Rep. 2020 Aug 6;10(1):13206. doi: 10.1038/s41598-020-69995-9.
The use of non-standard toxicity models is a hurdle in the early development of antimicrobial peptides towards clinical applications. Herein we report an extensive in vitro and in vivo toxicity study of a library of 24 peptide-based antimicrobials with narrow spectrum activity towards veterinary pathogens. The haemolytic activity of the compounds was evaluated against four different species and the relative sensitivity against the compounds was highest for canine erythrocytes, intermediate for rat and human cells and lowest for bovine cells. Selected peptides were additionally evaluated against HeLa, HaCaT and HepG2 cells which showed increased stability towards the peptides. Therapeutic indexes of 50-500 suggest significant cellular selectivity in comparison to bacterial cells. Three peptides were administered to rats in intravenous acute dose toxicity studies up to 2-8 × MIC. None of the injected compounds induced any systemic toxic effects in vivo at the concentrations employed illustrating that the correlation between the different assays is not obvious. This work sheds light on the in vitro and in vivo toxicity of this class of promising compounds and provides insights into the relationship between the different toxicity models often employed in different manners to evaluate the toxicity of novel bioactive compounds in general.
在将抗菌肽推向临床应用的早期开发中，非标准毒性模型的使用是一个障碍。在此，我们报告了对一组针对兽医病原体具有窄谱活性的 24 种基于肽的抗菌肽的广泛体外和体内毒性研究。评估了化合物对四种不同物种的溶血活性，对化合物的相对敏感性以犬红细胞最高，大鼠和人细胞居中，牛细胞最低。还选择了一些肽来评估 HeLa、HaCaT 和 HepG2 细胞，这些细胞对肽的稳定性更高。与细菌细胞相比，50-500 的治疗指数表明细胞具有显著的选择性。在静脉内急性剂量毒性研究中，将三种肽施用于大鼠，剂量高达 2-8×MIC。在所使用的浓度下，没有一种注射化合物在体内引起任何全身毒性作用，这表明不同测定之间的相关性并不明显。这项工作阐明了这类有前途的化合物的体外和体内毒性，并深入了解了通常以不同方式用于评估新型生物活性化合物毒性的不同毒性模型之间的关系。
