Stereochemical diversity of AI-2 analogs modulates quorum sensing in Vibrio harveyi and Escherichia coli

• Published in: Bioorganic & medicinal chemistry 2012-01, Vol.20 (1), p.249-256
• Main Authors: Rui, Fabio, Marques, João C., Miller, Stephen T., Maycock, Christopher D., Xavier, Karina B., Ventura, M. Rita
• Format: Article
• Language: English
• Subjects: agonists; AI-2; bacteria; Bacterial Proteins - agonists; Bacterial Proteins - metabolism; Biological and medical sciences; chemistry; Cyclization; DPD; DPD agonist; DPD analogs; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - metabolism; Escherichia coli Proteins - agonists; Escherichia coli Proteins - metabolism; Hexanes - chemistry; Homoserine - analogs & derivatives; Homoserine - chemical synthesis; Homoserine - chemistry; Homoserine - pharmacology; Lactones - chemical synthesis; Lactones - chemistry; Lactones - pharmacology; Medical sciences; methodology; Pentanes - chemistry; Pharmacology. Drug treatments; Quorum sensing; Quorum Sensing - drug effects; receptors; Repressor Proteins - agonists; Repressor Proteins - metabolism; Stereoisomerism; Vibrio - drug effects; Vibrio - metabolism; Vibrio harveyi; virulence
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.11.007

Bacteria coordinate population-dependent behaviors such as virulence by intra- and inter-species communication (quorum sensing). Autoinducer-2 (AI-2) regulates inter-species quorum sensing. AI-2 derives from the spontaneous cyclisation of linear (S)-4,5-dihydroxypentanedione (DPD) into two isomeric forms in dynamic equilibrium. Different species of bacteria have different classes of AI-2 receptors (LsrB and LuxP) which bind to different cyclic forms. In the present work, DPD analogs with a new stereocenter at C-5 (4,5-dihydroxyhexanediones (DHDs)) have been synthesized and their biological activity tested in two bacteria. (4S,5R)-DHD is a synergistic agonist in Escherichia coli (which contains the LsrB receptor), while it is an agonist in Vibrio harveyi (LuxP), displaying the strongest agonistic activity reported so far (EC50=0.65μM) in this organism. Thus, modification at C-5 opens the way to novel methods to manipulate quorum sensing as a method for controlling bacteria.