title: Building a Better Quaternary Ammonium Compound (QAC): Branched Tetracationic Antiseptic Amphiphiles.
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 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.
authors.affiliation: Department of Chemistry, Villanova University, 800 East Lancaster Avenue, Villanova, PA, 19085, USA.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Forman
authors.affiliation: Department of Chemistry, Temple University, 1901 North 13th Street, Philadelphia, PA, 19122, USA.
authors.forename: Megan C
authors.initials: MC
authors.lastname: Jennings
authors.affiliation: Department of Chemistry, Temple University, 1901 North 13th Street, Philadelphia, PA, 19122, USA. wwuest@temple.edu.
authors.forename: William M
authors.identifier: 0000-0002-5198-7744
authors.initials: WM
authors.lastname: Wuest
authors.affiliation: Department of Chemistry, Villanova University, 800 East Lancaster Avenue, Villanova, PA, 19085, USA. kevin.minbiole@villanova.edu.
authors.forename: Kevin P C
authors.identifier: 0000-0003-4263-9833
authors.initials: KP
authors.lastname: Minbiole
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D018441:Biofilms / Q000187:drug effects; D013293:Enterococcus faecalis / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D006461:Hemolysis; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D012756:Sheep; D013211:Staphylococcus aureus / Q000187:drug effects; D013501:Surface-Active Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000900:Anti-Bacterial Agents; D000644:Quaternary Ammonium Compounds; D013501:Surface-Active Agents
keywords: bacterial biofilms; disinfectants; methicillin-resistant Staphylococcus aureus (MRSA); quaternary ammonium compounds