Quorum-sensing inhibitors as anti-pathogenic drugs.
Quorum-sensing (QS) signalling systems of pathogens are central regulators for the expression of virulence factors and represent highly attractive targets for the development of novel therapeutics. In Pseudomonas aeruginosa, QS systems are also involved in elevated antibiotic tolerance of biofilms as well as elevated tolerance to the activity of the innate immune system. Gram-negative bacteria commonly use N-acyl homoserine lactones (AHL) as QS signal molecules. The use of signal molecule based drugs to attenuate bacterial pathogenecity rather than bacterial growth is attractive for several reasons, particularly considering the emergence of increasingly antibiotic-resistant bacteria. Compounds capable of this type of interference have been termed anti-pathogenic drugs. A large variety of synthetic AHL analogues and natural products libraries have been screened and a number of QS inhibitors (QSI) have been identified. Promising QSI compounds have been shown to make biofilms more susceptible to antimicrobial treatments, and are capable of reducing mortality and virulence as well as promoting clearance of bacteria in experimental animal models of infection.
Rasmussen
Thomas B
TB
Center for Biomedical Microbiology, BioCentrum-DTU, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
Givskov
Michael
M
D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000378:metabolism / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D008025:Ligases / Q000037:antagonists & inhibitors; D008666:Metalloendopeptidases / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology; D014774:Virulence
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D012097:Repressor Proteins; C080512:TraR protein, Agrobacterium tumefaciens; D015534:Trans-Activators; C064778:LuxR autoinducer binding proteins; C088386:homoserine lactone; C406735:AiiA protein, Bacillus; D008666:Metalloendopeptidases; D008025:Ligases; C449816:N-acylhomoserine lactone synthase; D015107:4-Butyrolactone