Modeling the effect of acylated homoserine lactone antagonists in Pseudomonas aeruginosa.
Pseudomonas aeruginosa is a gram-negative bacterium that causes serious illnesses, particularly in immunocompromised individuals, often with a fatal outcome. The finding that the acylated homoserine lactone quorum sensing (QS) system controls the production of virulence factors in P. aeruginosa makes this system a possible target for antimicrobial therapy. It has been suggested that an N-(3-oxododecanoyl)-homoserine lactone (3O-C12-HSL) antagonist, a QS blocker (QSB), would interfere efficiently with the quorum sensing system in P. aeruginosa and thus reduce the virulence of this pathogen. In this work, a mathematical model of the QS system in P. aeruginosa has been developed. The model was used to virtually add 3O-C12-HSL antagonists that differed in their affinity for the receptor protein and for their ability to mediate degradation of the receptor. The model suggests that very small differences in these parameters for different 3O-C12-HSL antagonists can greatly affect the success of QSB based inhibition of the QS system in P. aeruginosa. Most importantly, it is proposed that the ability of the 3O-C12-HSL antagonist to mediate degradation of LasR is the core parameter for successful QSB based inhibition of the QS system in P. aeruginosa. Finally, this study demonstrates that QSBs can shift the system to a low steady state, corresponding to an uninduced state and thus, suggests that the use of 3O-C12-HSL antagonists may constitute a promising therapeutic approach against P. aeruginosa involved infections.
Fagerlind
Magnus G
MG
Computational Molecular Biology, Department of Natural Sciences, University of Skövde, Skövde, Sweden. magnus.fagerlind@his.se
Nilsson
Patric
P
Harlén
Mikael
M
Karlsson
Sandra
S
Rice
Scott A
SA
Kjelleberg
Staffan
S
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D015195:Drug Design; D008954:Models, Biological; D008956:Models, Chemical; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000900:Anti-Bacterial Agents; C088386:homoserine lactone; D015107:4-Butyrolactone