AI-2 quorum-sensing inhibitors affect the starvation response and reduce virulence in several Vibrio species, most likely by interfering with LuxPQ.
The increase of disease outbreaks caused by Vibrio species in aquatic organisms as well as in humans, together with the emergence of antibiotic resistance in Vibrio species, 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 species, 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 affected neither 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 the Vibrio species 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.
Laboratory of Pharmaceutical Microbiology, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium.
Gilles
G
Brackman
Laboratory of Medicinal Chemistry, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium.
Shari
S
Celen
Laboratory of Aquaculture and Artemia Reference Center, Ghent University, Rozier 44, 9000 Ghent, Belgium.
Kartik
K
Baruah
Laboratory of Aquaculture and Artemia Reference Center, Ghent University, Rozier 44, 9000 Ghent, Belgium.
Peter
P
Bossier
Laboratory of Medicinal Chemistry, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium.
Serge
S
Van Calenbergh
Laboratory of Pharmaceutical Microbiology, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium.
Hans J
HJ
Nelis
Laboratory of Pharmaceutical Microbiology, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium.
Tom
T
Coenye
D000818:Animals; D001156:Artemia / Q000187:drug effects / Q000382:microbiology; D001426:Bacterial Proteins / Q000502:physiology; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D006714:Homoserine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000502:physiology; D007783:Lactones / Q000037:antagonists & inhibitors; D010641:Phenotype; D010770:Phosphotransferases / Q000502:physiology; D053038:Quorum Sensing / Q000187:drug effects / Q000502:physiology; D012263:Ribonucleosides / Q000737:chemistry / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology; D014733:Vibrio / Q000187:drug effects / Q000472:pathogenicity* / Q000502:physiology*; D014774:Virulence / Q000502:physiology
D001426:Bacterial Proteins; D007783:Lactones; C090749:LuxP protein, Vibrio; C091088:N-octanoylhomoserine lactone; D012263:Ribonucleosides; D014157:Transcription Factors; D006714:Homoserine; D010770:Phosphotransferases; C090750:luxQ protein, Vibrio harveyi