title: Modulation of the Substitution Pattern of 5-Aryl-2-Aminoimidazoles Allows Fine-Tuning of Their Antibiofilm Activity Spectrum and Toxicity.
abstract: We previously synthesized several series of compounds, based on the 5-aryl-2-aminoimidazole scaffold, that showed activity preventing the formation of Salmonella enterica serovar Typhimurium and Pseudomonas aeruginosa biofilms. Here, we further studied the activity spectrum of a number of the most active N1- and 2N-substituted 5-aryl-2-aminoimidazoles against a broad panel of biofilms formed by monospecies and mixed species of bacteria and fungi. An N1-substituted compound showed very strong activity against the biofilms formed by Gram-negative and Gram-positive bacteria and the fungus Candida albicans but was previously shown to be toxic against various eukaryotic cell lines. In contrast, 2N-substituted compounds were nontoxic and active against biofilms formed by Gram-negative bacteria and C. albicans but had reduced activity against biofilms formed by Gram-positive bacteria. In an attempt to develop nontoxic compounds with potent activity against biofilms formed by Gram-positive bacteria for application in antibiofilm coatings for medical implants, we synthesized novel compounds with substituents at both the N1 and 2N positions and tested these compounds for antibiofilm activity and toxicity. Interestingly, most of these N1-,2N-disubstituted 5-aryl-2-aminoimidazoles showed very strong activity against biofilms formed by Gram-positive bacteria and C. albicans in various setups with biofilms formed by monospecies and mixed species but lost activity against biofilms formed by Gram-negative bacteria. In light of application of these compounds as anti-infective coatings on orthopedic implants, toxicity against two bone cell lines and the functionality of these cells were tested. The N1-,2N-disubstituted 5-aryl-2-aminoimidazoles in general did not affect the viability of bone cells and even induced calcium deposition. This indicates that modulating the substitution pattern on positions N1 and 2N of the 5-aryl-2-aminoimidazole scaffold allows fine-tuning of both the antibiofilm activity spectrum and toxicity.
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Leuven, Belgium.
authors.forename: Elien
authors.initials: E
authors.lastname: Peeters
authors.affiliation: Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, KU Leuven, Leuven, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Hooyberghs
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Leuven, Belgium.
authors.forename: Stijn
authors.initials: S
authors.lastname: Robijns
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Leuven, Belgium.
authors.forename: Kai
authors.initials: K
authors.lastname: Waldrant
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Leuven, Belgium.
authors.forename: Ami
authors.initials: A
authors.lastname: De Weerdt
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Leuven, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Delattin
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Leuven, Belgium.
authors.forename: Veerle
authors.initials: V
authors.lastname: Liebens
authors.affiliation: Department of Molecular Microbiology, VIB, Leuven, Belgium.|Laboratory of Molecular Cell Biology, Department of Biology, KU Leuven, Leuven, Belgium.
authors.forename: Soňa
authors.initials: S
authors.lastname: Kucharíková
authors.affiliation: Department of Molecular Microbiology, VIB, Leuven, Belgium.|Laboratory of Molecular Cell Biology, Department of Biology, KU Leuven, Leuven, Belgium.
authors.forename: Hélène
authors.initials: H
authors.lastname: Tournu
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Leuven, Belgium.
authors.forename: Natalie
authors.initials: N
authors.lastname: Verstraeten
authors.affiliation: Educell, Trzin, Slovenia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Dovgan
authors.affiliation: Educell, Trzin, Slovenia.
authors.forename: Lenart
authors.initials: L
authors.lastname: Girandon
authors.affiliation: Educell, Trzin, Slovenia.|Faculty of Medicine, Institute of Cell Biology, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Fröhlich
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Leuven, Belgium.
authors.forename: Katrijn
authors.initials: K
authors.lastname: De Brucker
authors.affiliation: Department of Molecular Microbiology, VIB, Leuven, Belgium.|Laboratory of Molecular Cell Biology, Department of Biology, KU Leuven, Leuven, Belgium.
authors.forename: Patrick
authors.identifier: 0000-0002-1542-897X
authors.initials: P
authors.lastname: Van Dijck
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Michiels
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Leuven, Belgium.
authors.forename: Bruno P A
authors.initials: BP
authors.lastname: Cammue
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Leuven, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Thevissen
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Leuven, Belgium.
authors.forename: Jozef
authors.initials: J
authors.lastname: Vanderleyden
authors.affiliation: Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, KU Leuven, Leuven, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: Van der Eycken
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Department of Microbial and Molecular Systems, KU Leuven, Leuven, Belgium hans.steenackers@biw.kuleuven.be.
authors.forename: Hans P
authors.initials: HP
authors.lastname: Steenackers
mesh_terms: D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development; D012486:Salmonella typhimurium / Q000187:drug effects / Q000254:growth & development; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D013212:Staphylococcus epidermidis / Q000187:drug effects / Q000254:growth & development; D013329:Structure-Activity Relationship
chemical_list: D000890:Anti-Infective Agents; D007093:Imidazoles