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AI-2 quorum sensing inhibitors affect the starvation response and reduce virulence in several Vibrio species, most likely by interfering with LuxPQ

¹ Ghent University;
² Laboratorium voor Farmaceutische Microbiologie, Universiteit Gent

The increase of disease outbreaks caused by Vibrio spp. in aquatic organisms as well as in humans, together with the emergence of antibiotic resistance in Vibrio spp., has led to a growing interest in alternative disease control measures. Quorum sensing (QS) is a mechanism for regulating microbial gene expression in a cell-density dependent way. While there is good evidence for the involvement of auto-inducer 2 (AI-2) based interspecies QS in the control of virulence in multiple Vibrio spp., only few inhibitors of this system are known. From the screening of a small panel of nucleoside analogues for their ability to disturb AI-2 based QS, an adenosine derivative with a p-methoxyphenylpropionamide moiety at C-3', emerged as a promising hit. Its mechanism of inhibition was elucidated by measuring the effect on bioluminescence in a series of Vibrio harveyi AI-2 QS mutants. Our results indicate that this compound, as well as a truncated analogue lacking the adenine base, block AI-2 based QS without interfering with bacterial growth. The active compounds neither affected the bioluminescence system as such, nor the production of AI-2, but most likely interfered with the signal transduction pathway at the level of LuxPQ in V. harveyi. The most active nucleoside analogue (designated LMC-21) was found to reduce Vibrio spp. starvation response, to affect biofilm formation in Vibrio anguillarum, Vibrio vulnificus and Vibrio cholerae, to reduce pigment and protease production in V. anguillarum and to protect gnotobiotic Artemia from V. harveyi-induced mortality.

³ E-mail: tom.coenye{at}ugent.be