title: Structure-Resistance Relationships: Interrogating Antiseptic Resistance in Bacteria with Multicationic Quaternary Ammonium Dyes.
abstract: Bacterial resistance toward commonly used biocides is a widespread yet underappreciated problem, one which needs not only a deeper understanding of the mechanisms by which resistance proliferates, but also means for mitigation. To advance our understanding of this issue, we recognized a polyaromatic structural core analogous to activators of QacR, a negative transcriptional regulator of the efflux pump QacA, and envisioned a series of quaternary ammonium compounds (QACs) based on this motif. Using commercially available dye scaffolds, we synthesized and evaluated the antimicrobial activity of 52 novel QACs bearing 1-3 quaternary ammonium centers. Striking differences in antimicrobial activity against bacteria bearing QAC resistance genes have been observed, with up to a 125-fold increase in minimum inhibitory concentration (MIC) for select structures against bacteria known to bear efflux pumps. Based on these findings, general trends in structure-resistance relationships have been identified, laying the groundwork for future mechanistic studies.
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: Madison H
authors.initials: MH
authors.lastname: Fletcher
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, Villanova University, 800 East Lancaster Avenue, Villanova, PA, 19085, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Duggan
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.initials: KP
authors.lastname: Minbiole
authors.affiliation: Department of Chemistry, Temple University, 1901 North 13th Street, Philadelphia, PA, 19122, USA. wwuest@temple.edu.
authors.forename: William M
authors.initials: WM
authors.lastname: Wuest
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D001426:Bacterial Proteins / Q000378:metabolism; D004396:Coloring Agents / Q000737:chemistry*; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004396:Coloring Agents; D000644:Quaternary Ammonium Compounds
keywords: MRSA; antibiotic resistance; biocides; quaternary ammonium compounds