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Forman ME , Jennings MC , Wuest WM , Minbiole KP
Building a Better Quaternary Ammonium Compound (QAC): Branched Tetracationic Antiseptic Amphiphiles
ChemMedChem. 2016 Jul 5;11(13) :1401-5
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Abstract
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 mum, 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.
Notes
Forman, Megan E Jennings, Megan C Wuest, William M Minbiole, Kevin P C Research Support, U.S. Gov't, Non-P.H.S. ReseChemMedChem. 2016 Jul 5;11(13):1401-5. doi: 10.1002/cmdc.201600176. Epub 2016 Jun 1.arch Support, Non-U.S. Gov't