DIVINOCELL - Exploiting Gram-negative cell division targets in the test tube to obtain antimicrobial compounds

Summary:

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 companies in close collaboration with the 8 academic partners having well-proven expertise in molecular microbiology, protein chemistry, structural biology, biophysics, imaging and bioinformatics.

Problem:

Bacterial antibiotic resistance

Results:

DIVINOCELL will progress beyond the state-of-the-art in antimicrobial research by incorporating front-line technology into the knowledge on the Gram-negative division process to design and run screening assays and validate the resultant hits. Progress will be maximised by building compound collections for screening tailored to divisome and septum targets. DIVINOCELL will also perform lead improvement on selected hits.

Coordinator:

Partners:

participant institution