Antibiotics with pleiotropic activities: Daptomycin and amphiphilic glycopeptides

• Antragstellerin: Professorin Dr. Tanja Schneider
• Fachliche Zuordnung: Parasitologie und Biologie der Erreger tropischer Infektionskrankheiten
• Förderung: Förderung von 2008 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 33421847

The lipopeptide antibiotic daptomycin is clinically very effective against multiresistant gram-positive bacteria, however, its molecular mechanism of action is poorly understood holding off further rational drug development. In the first funding period we have shown that the cellular responses triggered by daptomycin are in part similar to those of glycopeptide antibiotics and defensins which act as cell wall biosynthesis inhibitors. However, we were unable to identify a molecular target; it appears possible that daptomycin forms an oligomer which inserts into the membrane and causes pleiotropic effects on cell wall biosynthesis and cell division, however, such a mode of action seems not to be consistent with the potency and specificity of daptomycin. In the second funding period we want to continue our search for a molecular target. In case a target cannot be found, we will substantiate the model of untargeted membrane insertion and subsequent pleiotropic effects. Confirming such a mechanism for an approved drug could represent a paradigm for the development of antimicrobial peptides (AMPs, defensins). AMPs are believed to act by such an unspecific, “dirty drug” like mechanism that is considered unsuitable for drug development. For a comprehensive understanding of pleiotropic mechanisms we want to compare new glycopeptide antibiotics with strong amphiphilic properties, which specifically block the cell wall precursor lipid II but retain activity against vancomycin resistant bacteria with modified lipid II structures, presumably through pleiotropic membrane effects.

• DFG-Verfahren: Forschungsgruppen
• Teilprojekt zu: FOR 854: Post-genomische Strategien für neue antibiotische Wirkstoffe und Zielstrukturen
• Großgeräte: upgrade for fluorescence microscopy
• Gerätegruppe: 5080 Optisches Mikroskopzubehör
• Beteiligte Person: Professor Dr. Hans-Georg Sahl