Abstract：
Carboxylic polyether ionophores (CPIs) are among the most prevalent agricultural antibiotics (notably in the US) and these compounds have been in use for decades. The potential to reposition CPIs beyond veterinary use, e. g. through chemical modifications to enhance their selectivity window, is an exciting challenge and opportunity, considering their general resilience towards resistance development. Given the very large societal impact of these somewhat controversial compounds, it is surprising that many aspects of their mechanisms and activities in cells remain unclear. Here, we report comparative biological activities of the CPI routiennocin and two stereoisomers, including its enantiomer. We used an efficient convergent synthesis strategy to access the compounds and conducted a broad survey of antibacterial activities against planktonic cells and biofilms as well as the compounds\' effects on mammalian cells, the latter assessed both via standard cell viability assays and broad morphological profiling. Interestingly, similar bioactivity of the enantiomeric pair was observed across all assays, strongly suggesting that chiral interactions do not play a decisive role in the mode of action. Overall, our findings are consistent with a mechanistic model involving highly dynamic behaviour of CPIs in biological membranes.
摘要：
羧酸聚醚离子载体(CPIs)是最普遍的农业抗生素(特别是在美国),并且这些化合物已经使用了几十年。重新定位超出兽医用途的CPI的潜力，例如，通过化学修饰来增强其选择性窗口，是一个令人兴奋的挑战和机遇，考虑到他们对阻力发展的总体韧性。考虑到这些有点争议的化合物的巨大社会影响，令人惊讶的是，它们在细胞中的机制和活性的许多方面仍不清楚。这里,我们报告了CPIroutiennocin和两种立体异构体的比较生物活性，包括其对映异构体。我们使用了一种有效的聚合合成策略来获得这些化合物，并对针对浮游细胞和生物膜的抗菌活性以及化合物对哺乳动物细胞的影响进行了广泛的调查。后者通过标准细胞活力测定和广泛的形态学分析进行评估。有趣的是,在所有测定中观察到对映体对的相似生物活性，强烈表明手性相互作用在作用方式中不起决定性作用。总的来说,我们的发现与涉及细胞膜中CPIs高度动态行为的机械模型一致。
