Exotoxin A from Pseudomonas aeruginosa; mechanism and inhibition
Using a range of computational tools the mechanism of action of the toxins are explored, and new inhibitors targetting the NADP binding site identified using in silico docking teachniques.
The project is funded by the Swedish Research Council (Framework grant 2014-3914), VGR/MSCA-fp7 (MoRE programme) and CARe.
Participants: Prof Leif A. Eriksson (PI) and Dr Patricia Saenz-Mendez, UdelaR, Montevideo, Uruguay.
Exotoxin A of P.aeruginosa, and the closely related Cholix toxin and Diptheria toxin, are ADP-ribosylating enzymes that attack the uniquely modifed histidine derivative dihthamide in eukaryotic Elongation Fator 2 (eEF2), and consitute a major virulence factor of the corresponding pathogens. By modifying eEF2, the toxins efficiently stop protein synthesis in the host cells, leading to apoptosis and supply of nutrients to the bacteria. Using a range of computational tools the mechanism of action of the toxins are explored, and new inhibitors targetting the NADP binding site identified using in silico docking teachniques. Together with SciLifeLab (KI) an assay for assessing new proposed binders is being developed. We are furhtermore extending the use of inverse docking techniques to explore selectivity vs broad hitting potential of identified compounds, and to screen binders for adverse side effects.