Exploiting Gram-negative cell division targets in .. (DIVINOCELL)
Exploiting Gram-negative cell division targets in the test tube to obtain anti-microbial compounds
Start date: Mar 1, 2009,
End date: Aug 31, 2013
The DIVINOCELL project will identify novel Gram-negative targets by exploiting the components of the divisome, their activities and interactions. It will also design selective assays for screening and will obtain a new class of antimicrobials: compounds to block bacterial division. New medicines to attack Gram-negative pathogens will decrease the burden of infectious disease and have a highly beneficial social and economic impact in Europe and beyond. Cell division is an essential and still underexploited process with excellent properties to yield new inhibitors to attack infection by blocking the proliferation of pathogens. Inhibitors directed against bacterial division targets, that are not present in eukaryotic cells, will be both effective and innocuous to humans and animals. In addition, as many of their structures will be based on interaction domains and synthetic scaffolds, they will generate resistance at levels lower than the present antibiotics. DIVINOCELL will apply existing and new knowledge on the molecular biology of Gram-negative cell division as well as novel analytical (nanodiscs), bioinformatic (molecular dynamics), structural (membrane protein crystals) and imaging (lanthanide staining) tools to exploit in the test tube the structures and interactions of targets in the divisome and the septum. DIVINOCELL will develop potent systematic screening assays and will use them to select compounds specifically tailored to inhibit the division of Gram-negatives (not precluding broad spectrum ones). Secondary activity and cell assays, based on the properties of bacterial division, will be generated to validate hits and advance them to leads. The medicinal properties of selected leads will be improved. The translational steps of the project will be developed by 4 SMEs in close collaboration with the 8 academic partners having well-proven expertise in molecular microbiology, protein chemistry, structural biology, biophysics, imaging and bioinformatics.
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