Design of peptide-derived antibiotics that block interactions between bacterial cell division proteins

By Felix Paulussen

Cell division in bacteria is coordinated by numerous membrane-associated proteins that assemble at the middle of a cell forming a complex called divisome. The divisome coordinates the spatial and temporal organization of cell division in a series of defined steps. An imbalance in these activities ultimately leads to cell death and thus prevents spreading of bacteria. Hence, targeting the cell division machinery is a promising way to obtain new antibiotics.

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Figure 1:A Regular shaped E.coli cells.   BE.coli cells treated with frontrunner compound can’t divide properly anymore and show a different cell shape. C  Model of divisome complex with targeted FtsQBL complex in the center (grey, green, orange).

 

A core subcomplex of the divisome consists of three subunits: FtsQ, FtsB and FtsL that regulates divisome assembly and peptidoglycan synthesis. Previous work provided insight into the three-dimensional structure of the complex and revealed regions important for the interaction (and thus complex formation) of the three proteins. Based on this structural insight peptide inspired compounds that bind one of the involved proteins and thus potentially prevent divisome assembly and bacterial proliferation have been synthesized and binding to the target protein optimized. Competition experiments showed efficient prevention of complex assembly in vitro. The developed compounds were also tested for their effect on bacterial growth and cell morphology. It was found that the frontrunner compounds successfully inhibited bacterial growth and also altered the shape of the cells thereby validating the relevance of the target. In the future these compounds will be tested in more complex biological model systems and their mechanism of action investigated in cell based assays.

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 713669.

 

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