title: Beyond paraquats: dialkyl 3,3'- and 3,4'-bipyridinium amphiphiles as antibacterial agents.
abstract: Dialkyl 4,4'-bipyridinium compounds, known as 'paraquats' (PQs), have a long history of use as herbicides, as redox indicators, and more recently as potent antibacterial agents. However, due to their ability to form reactive oxygen species (ROS) in vivo, PQs are also known to be toxic. We proposed that altering the electrochemical properties of PQ, specifically by preparing isomeric bipyridinium structures with 3,3'- and 3,4'-substitution of the nitrogen heteroatoms on the biaryl core, would maintain antibacterial activity, yet decrease toxicity. We have thus prepared a series of 17 amphiphiles, dubbed 'metaquat' (MQ) and 'parametaquat' (PMQ), respectively, and investigated their antibacterial and electrochemical properties. Optimal inhibition of bacterial growth was observed in symmetric, biscationic structures; minimum inhibitory concentration (MIC) values measured as low as 0.5 μM against both Gram-positive and Gram-negative bacteria for the compound PMQ-11,11. Electrochemical analysis demonstrated the redox properties of the dialkyl 3,3'- and 3,4'-bipyridinium amphiphiles to be distinct from those of the 4,4'-bipyridinium isomer. Thus MQ and PMQ amphiphiles maintain the strong antibacterial activity of the PQ isomers, but show promise for reduced ROS toxicity.
authors.affiliation: Department of Chemistry, Villanova University, Villanova, PA 19085, United States.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Ator
authors.affiliation: Department of Chemistry, Temple University, Philadelphia, PA 19122, United States.
authors.forename: Megan C
authors.initials: MC
authors.lastname: Jennings
authors.affiliation: Department of Chemistry, Villanova University, Villanova, PA 19085, United States.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: McGettigan
authors.affiliation: Department of Chemistry, Villanova University, Villanova, PA 19085, United States.
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Paul
authors.affiliation: Department of Chemistry, Temple University, Philadelphia, PA 19122, United States. Electronic address: tud51221@temple.edu.
authors.forename: William M
authors.initials: WM
authors.lastname: Wuest
authors.affiliation: Department of Chemistry, Villanova University, Villanova, PA 19085, United States. Electronic address: kevin.minbiole@villanova.edu.
authors.forename: Kevin P C
authors.initials: KP
authors.lastname: Minbiole
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D013293:Enterococcus faecalis / Q000187:drug effects* / Q000254:growth & development; D004926:Escherichia coli / Q000187:drug effects* / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development; D011726:Pyridinium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D011726:Pyridinium Compounds
keywords: Amphiphile; Antibacterial; Bipyridinium; Metaquat; Paraquat