Synthesis of antimicrobial glucosamides as bacterial quorum sensing mechanism inhibitors

Nripendra N Biswas; Tsz Tin Yu; Önder Kimyon; Shashidhar Nizalapur; Christopher R Gardner; Mike Manefield; Renate Griffith; David StC Black; Naresh Kumar

doi:10.1016/j.bmc.2016.12.024

Synthesis of antimicrobial glucosamides as bacterial quorum sensing mechanism inhibitors

Bioorg Med Chem. 2017 Feb 1;25(3):1183-1194. doi: 10.1016/j.bmc.2016.12.024. Epub 2016 Dec 21.

Authors

Nripendra N Biswas¹, Tsz Tin Yu¹, Önder Kimyon², Shashidhar Nizalapur¹, Christopher R Gardner¹, Mike Manefield², Renate Griffith³, David StC Black¹, Naresh Kumar⁴

Affiliations

¹ School of Chemistry, University of New South Wales, Sydney, NSW, Australia.
² School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
³ Department of Pharmacology, School of Medical Science, University of New South Wales, Sydney, NSW, Australia.
⁴ School of Chemistry, University of New South Wales, Sydney, NSW, Australia. Electronic address: n.kumar@unsw.edu.au.

PMID: 28049617
DOI: 10.1016/j.bmc.2016.12.024

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.

Keywords: Antimicrobial; Biofilm; Glucosamide; Quorum sensing.

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Dose-Response Relationship, Drug
Escherichia coli / drug effects*
Glucosamine / chemical synthesis
Glucosamine / chemistry
Glucosamine / pharmacology*
Microbial Sensitivity Tests
Molecular Structure
Pseudomonas aeruginosa / drug effects*
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Glucosamine