title: Scaffold-Hopping of Multicationic Amphiphiles Yields Three New Classes of Antimicrobials.
abstract: Quaternary ammonium compounds (QACs) are a vital class of antiseptics. Recent investigations into their construction are uncovering novel and potent multicationic variants. Based on a trisQAC precedent, we have implemented a scaffold-hopping approach to develop alternative QAC architectures that display 1-3 long alkyl chains in specific projections from cyclic and branched core structures bearing 3-4 nitrogen atoms. The preparation of 30 QAC structures allowed for correlation of scaffold structure with antimicrobial activity. We identified QACs with limited conformational flexibility that have improved bioactivity against planktonic bacteria as compared to their linear counterparts. We also confirmed that resistance, as evidenced by an increased minimum inhibitory concentration (MIC) for methicillin-resistant Staphylococcus aureus (MRSA) compared to methicillin-susceptible Staphylococcus aureus (MSSA), can reduce efficacy up to 64-fold for monocationic QACs. Differentiation of antimicrobial and anti-biofilm activity, however, was not observed, suggesting that these compounds utilize a non-specific mode of eradication.
authors: Department of Chemistry, Villanova University, 800 E. Lancaster Avenue, Villanova, PA, 19085, USA.
authors: Myles A
authors: MA
authors: Mitchell
authors: Department of Chemistry, Villanova University, 800 E. Lancaster Avenue, Villanova, PA, 19085, USA.
authors: Anthony A
authors: AA
authors: Iannetta
authors: Department of Chemistry, Temple University, 1901 N. 13th Street, Philadelphia, PA, 19122, USA.
authors: Megan C
authors: MC
authors: Jennings
authors: Department of Chemistry, Temple University, 1901 N. 13th Street, Philadelphia, PA, 19122, USA.
authors: Madison H
authors: MH
authors: Fletcher
authors: Department of Chemistry, Temple University, 1901 N. 13th Street, Philadelphia, PA, 19122, USA. wwuest@temple.edu.
authors: William M
authors: WM
authors: Wuest
authors: Department of Chemistry, Villanova University, 800 E. Lancaster Avenue, Villanova, PA, 19085, USA. kevin.minbiole@villanova.edu.
authors: Kevin P C
authors: KP
authors: Minbiole
mesh_terms: D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects; D002412:Cations / Q000737:chemistry; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000502:physiology; D008826:Microbial Sensitivity Tests; D000644:Quaternary Ammonium Compounds / Q000737:chemistry*
chemical_list: D000890:Anti-Infective Agents; D002412:Cations; D000644:Quaternary Ammonium Compounds
keywords: amphiphile; antimicrobial; biofilm; multiQAC; triscationic