Development of inhibitors targetting Leukotoxins
In this project we employ a range of bioinformatics tools such as homology modelling, protein-protein docking, binding site analyses and virtual screening/docking, as well as extensive molecular dynamics simulations, to identify new candidate drugs that are able to disrupt the alpha-beta-dimer interactions and thus disbale pore formation and reduce the bacterial virulence.
The project is funded by the Swedish Research Council (Framework grant 2014-3914) and CARe.
Participants: Prof Leif A. Eriksson (PI), Prof Johan Gottfries and Sonali Chavan (PhD student), Dep. of Chemistry and Molecular Biology at GU.
Leukotoxins are secreted virulence factors from several severe pathogens, incuding methicillin resistant Staphillococcus aureus (MRSA). The leukotixins are secreted as alpha or beta monomers and merge into a pore-forming octamer with alternating alpha- and beta- monomers. Upon pore formation, the attacked host cells are depleted of their contents and the pathogen thus able to acquire necessary nutrients for continued growth and invasion. In this project we employ a range of bioinformatics tools such as homology modelling, protein-protein docking, binding site analyses and virtual screening/docking, as well as extensive molecular dynamics simulations, to identify new candidate drugs that are able to disrupt the alpha-beta-dimer interactions and thus disbale pore formation and reduce the bacterial virulence. This in turn will provide more time for the host defense machinery to attack and kill the invasive pathogens. By addressing secreted enzymes we hope to be able to avoid feedback mechanisms and development of resistance towards the identified compounds.