Bacterial infections, whether in the hospital or in healthy populations, still pose one of the biggest threats to healthcare systems. In particular, the continuing emergence of antibiotic-resistant strains in most pathogenic bacteria creates a need for novel anti-infective strategies. In contrast to protein virulence factors, the cell wall glycopolymers (CWGs) of bacteria have not been studied in detail with respect to their roles in colonization and infection for commensal and pathogenic bacterial species. However, CWGs are key constituents of the cell envelope and major surface determinants at the host-pathogen interface, especially in Gram-positive bacteria. For example, we were able to demonstrate that in the major human pathogenStaphylococcus aureus, a CWG termed teichoic acid (WTA) is a non-protein adhesin that interacts with a novel receptor on host cells, exerting a key role in S. aureus nasal colonization. We propose that these CWG receptors generally play important roles not only in host-pathogen interactions by influencing infection outcomes, but they also affect the bacterial species interference in different host niches. Consequently, bacterial competition for CWG receptors could significantly influence the microbiota composition, e.g., in the nasal cavity. We want to elucidate the structural prerequisites of CWG-receptor interaction in detail and try to unravel its impact on bacterial infections, microbiota composition and related host responses.
We propose targeting such glycopolymer/host-receptor interaction as a novel strategy to prevent or control e.g. S. aureus nasal colonizatio . This novel concept could have a considerable impact as it directs the attention to bacterial glycopolymer/host-receptor interactions, a so far neglected field with a huge potential for therapeutic interventions.
In addition, we want to elucidate the role of WTA in modulation of the immune response during staphylococcal infections. We are currently trying to decipher the regulation of WTA biosynthesis during an infection and the impact of strain specific differences of WTA biosynthesis on the virulence of S. aureus strains. We have recently shown that WTA is an antigen that can be loaded on MHC II molecules in antigen presenting cells and activate T cells in a process that requires zwitterionic charge centers in the repeating units of the WTA polymer backbone.
Adaptation of WTA biosynthesis to antibiotic resistance stress plays an important role in daptomycin insensitivity. Daptomycin is a last resort antibiotic for treatment of severe MRSA infections and treatment failure a severe clinical problem. Therefore, we aim at understanding the mechanisms by which WTA biosynthesis is induced under daptomycin challenge. Several daptomycin insensitive clinical S. aureus isolates exhibit an increased WTA incorporation into the cell wall which sterically hinders daptomycin binding to the staphylococcal cell membrane.