title: Evaluation of the toxicity of 2-aminoimidazole antibiofilm agents using both cellular and model organism systems.
abstract: Biofilm formation is a ubiquitous bacterial defense mechanism and has been shown to be a primary element in the antibiotic resistance of many human diseases, especially in the case of nosocomial infections. Recently, we have developed several compound libraries that are extremely effective at both dispersing preexisting biofilms and also inhibiting their initial formation. In addition to their antibiofilm properties, some of these molecules are able to resensitize resistant bacterial strains to previously ineffective antibiotics and are being assessed as adjuvants. In this study, we evaluated the toxic effects of three of our most effective 2-aminoimidazole compounds (dihydrosventrin, RA, and SPAR) using a rapid pipeline that combines a series of assays. A methylthiazolyldiphenyl-tetrazolium assay, using the HaCaT keratinocyte cell line was used to determine epidermal irritants and was combined with Caenorhabditis elegans fecundity assays that demonstrated the effects of environmental exposure to various concentrations of these molecules. In each case, the assays showed that the compounds did not exhibit toxicity until they reached well above their current biofilm dispersion/inhibition concentrations. The most effective antibiofilm compound also had significant effects when used in conjunction with several standard antibiotics against resistant bacteria. Consequently, it was further investigated using the C. elegans assay in combination with different antibiotics and was found to maintain the same low level of toxicity as when acting alone, bolstering its candidacy for further testing as an adjuvant.
authors.affiliation: Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695-7622, USA.
authors.forename: Sean D
authors.initials: SD
authors.lastname: Stowe
authors.forename: Ashley T
authors.initials: AT
authors.lastname: Tucker
authors.forename: Richele
authors.initials: R
authors.lastname: Thompson
authors.forename: Amanda
authors.initials: A
authors.lastname: Piper
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Richards
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rogers
authors.forename: Laura D
authors.initials: LD
authors.lastname: Mathies
authors.forename: Christian
authors.initials: C
authors.lastname: Melander
authors.forename: John
authors.initials: J
authors.lastname: Cavanagh
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000633:toxicity*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000633:toxicity*; D018441:Biofilms / Q000187:drug effects*; D017173:Caenorhabditis elegans; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure; D005298:Fertility / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000633:toxicity*; D015603:Keratinocytes / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D018675:Toxicity Tests
chemical_list: D000277:Adjuvants, Pharmaceutic; D000900:Anti-Bacterial Agents; D007093:Imidazoles; D013778:Tetrazolium Salts; D013844:Thiazoles; C014973:2-aminoimidazole; C022616:thiazolyl blue