A structurally unrelated mimic of a Pseudomonas aeruginosa acyl-homoserine lactone quorum-sensing signal.
The pathogenic bacterium Pseudomonas aeruginosa uses acyl-homoserine lactone quorum-sensing signals to coordinate the expression of a battery of virulence genes in a cascade of regulatory events. The quorum-sensing signal that triggers the cascade is N-3-oxo-dodecanoyl homoserine lactone (3OC12-HSL), which interacts with two signal receptor-transcription factors, LasR and QscR. This signal is base labile, and it is degraded by mammalian PON lactonases. We have identified a structurally unrelated triphenyl mimic of 3OC12-HSL that is base-insensitive and PON-resistant. The triphenyl mimic seems to interact specifically with LasR but not with QscR. In silico analysis suggests that the mimic fits into the 3OC12-HSL-binding site of LasR and makes key contacts with LasR. The triphenyl mimic is an excellent scaffold for developing quorum-sensing inhibitors, and its stability and potency make it ideal for biotechnology uses such as heterologous gene expression.
Müh
Ute
U
Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, MA 02139, USA.
Hare
Brian J
BJ
Duerkop
Breck A
BA
Schuster
Martin
M
Hanzelka
Brian L
BL
Heim
Roger
R
Olson
Eric R
ER
Greenberg
E Peter
EP
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D006714:Homoserine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D053038:Quorum Sensing / Q000502:physiology*; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism
D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C080365:LasR protein, Pseudomonas aeruginosa; C109860:N-(3-oxododecanoyl)homoserine lactone; C434259:QscR protein, Pseudomonas aeruginosa; D012097:Repressor Proteins; D015534:Trans-Activators; D006714:Homoserine; D015107:4-Butyrolactone