Abstract:
Staphylococcus aureus is a human commensal and major human pathogen. With the emergence of drug resistant strains, the development of alternative therapeutics becomes increasingly urgent. In order to adapt to the changing parameters of its surrounding S. aureus must modulate its surface properties accordingly. A central component of the S. aureus cell wall is the wall teichoic acid (WTA) consisting of ribitol-phosphate repeats that are further modified with D-alanine and N-acetylglucosamine (GlcNAc) residues. WTA has been identified as a crucial molecule for host colonization, β-lactam-resistance, bacteriophage-mediated horizontal gene transfer, and immune recognition.
In our recent studies, we could provide insight into the biochemistry and physiological impact of WTA glycosylation by employing microbiological, structure biological, and immunological techniques. Attachment of β-1,4-GlcNAc to WTA occurs by the housekeeping enzyme TarS. This default glycosylation can be altered by certain accessory glycosyltransferases. By identifying the prophage-encoded glycosyltransferase TarP, attaching β-1,3-GlcNAc, we demonstrated how mobile genetic elements are able to manipulate the glycocode of their bacterial host. TarP glycosylation lead to reduced immunogenicity in mice, which was reflected by low anti TarP-WTA-antibodies present in human sera. This remarkable link between WTA-glycosylation and the adaptive immune system might be exploited for the development of an S. aureus vaccine in the future. Furthermore, glycosylation by the alternative glycosyltransferases, TarM or TarP leads to podovirus resistance and, in case of TarP, weakened phage-mediated acquisition of genetic elements.
WTA glycosyltransferases show homotrimeric superstructures that are formed by unique trimerization domains whose physiological role remains to be elucidated. The obtained high-resolution insights into the substrate enzyme complex could guide structure based-strategies to identify potential inhibitors of WTA glycosyltransferases, which potentially attenuate S. aureus virulence or resensibilize them to clinically used antibiotics.