Forman Megan E, Jennings Megan C, Wuest William M, Minbiole Kevin P C
Department of Chemistry, Villanova University, 800 East Lancaster Avenue, Villanova, PA, 19085, USA.
Department of Chemistry, Temple University, 1901 North 13th Street, Philadelphia, PA, 19122, USA.
ChemMedChem. 2016 Jul 5;11(13):1401-5. doi: 10.1002/cmdc.201600176. Epub 2016 Jun 1.
Bacteria contaminate surfaces in a wide variety of environments, causing severe problems across a number of industries. In a continuation of our campaign to develop novel antibacterial quaternary ammonium compounds (QACs) as useful antiseptics, we have identified a starting material bearing four tertiary amines, enabling the rapid synthesis of several tris- and tetracationic QACs. Herein we report the synthesis and biological activity of a series of 24 multiQACs deemed the "superT" family, and an investigation of the role of cationic charge in antimicrobial and anti-biofilm activity, as well as toxicity. This class represents the most potent series of QACs reported to date against methicillin-resistant Staphylococcus aureus (MRSA), with minimum inhibitory concentrations (MICs) and minimum biofilm eradication concentrations (MBECs) as low as 0.25 and 25 μm, respectively. Based on the significant cell-surface-charge differences between bacterial and eukaryotic cells, in certain cases we observed excellent efficacy-to-toxicity profiles, exceeding a 100-fold differential. This work further elucidates the chemical underpinnings of disinfectant efficacy versus toxicity based on cationic charge.
细菌在各种各样的环境中污染表面,在许多行业中引发严重问题。在我们开发新型抗菌季铵化合物(QACs)作为有效防腐剂的活动的延续中,我们确定了一种带有四个叔胺的起始原料,能够快速合成几种三阳离子和四阳离子QACs。在此,我们报告了一系列被称为“superT”家族的24种多QACs的合成及生物活性,以及对阳离子电荷在抗菌和抗生物膜活性以及毒性中的作用的研究。此类化合物是迄今为止报道的对耐甲氧西林金黄色葡萄球菌(MRSA)最有效的QACs系列,其最低抑菌浓度(MICs)和最低生物膜根除浓度(MBECs)分别低至0.25和25μm。基于细菌细胞和真核细胞之间显著的细胞表面电荷差异,在某些情况下,我们观察到了出色的疗效与毒性概况,差异超过100倍。这项工作进一步阐明了基于阳离子电荷的消毒剂疗效与毒性的化学基础。