title: Amphipathic guanidine-embedded glyoxamide-based peptidomimetics as novel antibacterial agents and biofilm disruptors.
abstract: Antimicrobial resistance in bacteria is becoming increasingly prevalent, posing a critical challenge to global health. Bacterial biofilm formation is a common resistance mechanism that reduces the effectiveness of antibiotics. Thus, the development of compounds that can disrupt bacterial biofilms is a potential strategy to combat antimicrobial resistance. We report herein the synthesis of amphipathic guanidine-embedded glyoxamide-based peptidomimetics via ring-opening reactions of N-naphthoylisatins with amines and amino acids. These compounds were investigated for their antibacterial activity by the determination of minimum inhibitory concentration (MIC) against S. aureus and E. coli. Compounds 35, 36, and 66 exhibited MIC values of 6, 8 and 10 μg mL-1against S. aureus, respectively, while compounds 55 and 56 showed MIC values of 17 and 19 μg mL-1against E. coli, respectively. Biofilm disruption and inhibition activities were also evaluated against various Gram-positive and Gram-negative bacteria. The most active compound 65 exhibited the greatest disruption of established biofilms by 65% in S. aureus, 61% in P. aeruginosa, and 60% in S. marcescens respectively, at 250 μM concentration, while compound 52 inhibited the formation of biofilms by 72% in S. marcescens at 250 μM. We also report here the in vitro toxicity against MRC-5 human lung fibroblast cells. Finally, the pore forming capability of the three most potent compounds were tested using tethered bilayer lipid membrane (tBLM) technology.
authors.affiliation: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia. n.kumar@unsw.edu.au.
authors.forename: Shashidhar
authors.initials: S
authors.lastname: Nizalapur
authors.affiliation: School of Biotechnology and Biomolecular Sciences, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Onder
authors.initials: O
authors.lastname: Kimyon
authors.affiliation: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia. n.kumar@unsw.edu.au.
authors.forename: Eugene
authors.initials: E
authors.lastname: Yee
authors.affiliation: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia. n.kumar@unsw.edu.au.
authors.forename: Kitty
authors.initials: K
authors.lastname: Ho
authors.affiliation: Molecular Biosciences Research Team, School of Life Sciences, University of Technology Sydney, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Berry
authors.affiliation: School of Biotechnology and Biomolecular Sciences, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Mike
authors.initials: M
authors.lastname: Manefield
authors.affiliation: Molecular Biosciences Research Team, School of Life Sciences, University of Technology Sydney, Australia.
authors.forename: Charles G
authors.identifier: http://orcid.org/0000-0003-3608-5440
authors.initials: CG
authors.lastname: Cranfield
authors.affiliation: School of Optometry and Vision Science, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Willcox
authors.affiliation: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia. n.kumar@unsw.edu.au.
authors.forename: David StC
authors.initials: DS
authors.lastname: Black
authors.affiliation: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia. n.kumar@unsw.edu.au.
authors.forename: Naresh
authors.identifier: http://orcid.org/0000-0002-0951-9621
authors.initials: N
authors.lastname: Kumar
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects; D019791:Guanidine / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D057786:Peptidomimetics; D013453:Sulfonylurea Compounds; C032160:glyoxamide; D019791:Guanidine