“Novel points of attack” – Exploiting capsule biosynthesis in Streptococcus pneumoniae for antibacterial treatment

Synthesis of a polysaccharide capsule is crucial for Pneumococci to resist the immune system during infection. Whereas capsules have been successful targets for vaccines, biosynthetic reactions and mechanisms regulating capsule expression have not been investigated as potential therapeutic targets so far. Most S. pneumoniae serotypes produce capsular polysaccharides via the Wzx/Wzy-dependent pathway. In this case, building blocks are assembled on undecaprenyl phosphate at the inner side of the cytoplasmic membrane, translocated and polymerized in a non-processive manner on the exterior of the cell [2]. Enzymes of the LytR-CpsA-Psr (LCP) family are presumed to catalyze transfer and covalent linkage of capsular polysaccharides to peptidoglycan under release of the lipid carrier. However, biochemical evidence and molecular details for these reactions are lacking.

Modulation of cell envelope biosynthesis processes by glycopeptide antibiotics

Glycopeptide antibiotics are drugs of last resort for the treatment of infections caused by resistant Gram-positive bacteria. Despite tremendous research on the molecular mechanisms of action, glycopeptide induced effects leading to cell death are not fully elucidated. Aim of the TRR261-StartUp Research Project is to arrive at a better understanding of the cellular mechanisms underlying the mode of action of and mechanisms of resistance towards teicoplanin. To this end, the role of so far uncharacterized proteins involved in producer-self immunity and resistance will be studied.

Mechanism of action analyses of novel cell wall active compounds

Bacterial cell wall biosynthesis represents a most prominent target pathway for antibacterial intervention. Enzymes of the multi-enzyme biosynthetic machinery, as well as intermediates represent outstanding target molecules since they are often essential for bacterial viability and no homologous structures are present in humans. Target identification and detailed knowledge of the molecular mode of action of new antibiotics are integral components of the drug development process. Next to the essential peptidoglycan, wall teichoic and lipoteichoic acids, capsular polysaccharides are yet another highly important cell wall polymer of Gram-positive bacteria. These cell wall biosynthesis pathways include, besides mere antibiotic targets, intervention points for pathoblockers or antivirulence strategies.