title: Synthesis of antimicrobial glucosamides as bacterial quorum sensing mechanism inhibitors.
abstract: Bacteria communicate with one another and regulate their pathogenicity through a phenomenon known as quorum sensing (QS). When the bacterial colony reaches a threshold density, the QS system induces the production of virulence factors and the formation of biofilms, a powerful defence system against the host's immune responses. The glucosamine monomer has been shown to disrupt the bacterial QS system by inhibiting autoinducer (AI) signalling molecules such as the acyl-homoserine lactones (AHLs). In this study, the synthesis of acetoxy-glucosamides 8, hydroxy-glucosamides 9 and 3-oxo-glucosamides 12 was performed via the 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) and N,N'-dicyclohexylcarbodiimide (DCC) coupling methods. All of the synthesized compounds were tested against two bacterial strains, P. aeruginosa MH602 (LasI/R-type QS) and E. coli MT102 (LuxI/R-type QS), for QS inhibitory activity. The most active compound 9b showed 79.1% QS inhibition against P. aeruginosa MH602 and 98.4% against E. coli MT102, while compound 12b showed 64.5% inhibition against P. aeruginosa MH602 and 88.1% against E. coli MT102 strain at 2mM concentration. The ability of the compounds to inhibit the production of the virulence factor pyocyanin and biofilm formation in the P. aeruginosa (PA14) strain was also examined. Finally, computational docking studies were performed with the LasR receptor protein.
authors.affiliation: School of Chemistry, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Nripendra N
authors.initials: NN
authors.lastname: Biswas
authors.affiliation: School of Chemistry, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Tsz Tin
authors.initials: TT
authors.lastname: Yu
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Önder
authors.initials: Ö
authors.lastname: Kimyon
authors.affiliation: School of Chemistry, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Shashidhar
authors.initials: S
authors.lastname: Nizalapur
authors.affiliation: School of Chemistry, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Gardner
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Mike
authors.initials: M
authors.lastname: Manefield
authors.affiliation: Department of Pharmacology, School of Medical Science, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Renate
authors.initials: R
authors.lastname: Griffith
authors.affiliation: School of Chemistry, University of New South Wales, Sydney, NSW, Australia.
authors.forename: David StC
authors.initials: DS
authors.lastname: Black
authors.affiliation: School of Chemistry, University of New South Wales, Sydney, NSW, Australia. Electronic address: n.kumar@unsw.edu.au.
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects*; D005944:Glucosamine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D005944:Glucosamine
keywords: Antimicrobial; Biofilm; Glucosamide; Quorum sensing