Teichoic acids are temporal and spatial regulators of peptidoglycan cross-linking in Staphylococcus aureus

Abstract

The cell wall of Staphylococcus aureus is characterized by an extremely high degree of cross-linking within its peptidoglycan (PGN). Penicillin-binding protein 4 (PBP4) is required for the synthesis of this highly cross-linked peptidoglycan. We found that wall teichoic acids, glycopolymers attached to the peptidoglycan and important for virulence in Gram-positive bacteria, act as temporal and spatial regulators of PGN metabolism, controlling the level of cross-linking by regulating PBP4 localization. PBP4 normally localizes at the division septum, but in the absence of wall teichoic acids synthesis, it becomes dispersed throughout the entire cell membrane and is unable to function normally. As a consequence, the peptidoglycan of TagO null mutants, impaired in wall teichoic acid biosynthesis, has a decreased degree of cross-linking, which renders it more susceptible to the action of lysozyme, an enzyme produced by different host organisms as an initial defense against bacterial infection.

Methicillin resistance in Staphylococcus aureus requires glycosylated wall teichoic acids

“…Because the susceptibility phenotype seems directly attributable to the absence of the β-O-GlcNAc modifications on WTAs, we propose a scaffolding role for β-O-GlcNAcylated WTAs in methicillin resistance. Consistent with this hypothesis, it has been previously speculated that WTAs can scaffold PG synthesis and degradation proteins (11,(34)(35)(36). Moreover, a recent paper has shown that both PBP2a and FmtA directly bind WTAs in vitro (Fig.…”

Compound-gene interaction mapping reveals distinct roles for Staphylococcus aureus teichoic acids

“…3A), which encodes the machinery that installs D-alanines on both LTAs and WTAs (6). Because Dlt null mutants are temperature-sensitive, there were almost no insertions in the dlt operon in the untreated library even though this modification is not essential in a wild-type background (7,24). Therefore, the genome-wide growth depletion analysis did not provide information about possible synthetic interactions between the dltABCD genes and WTAs.…”

“…connection between two pathways, PG and WTA biosynthesis, that are proposed to be functionally coupled (10,24,34).…”

New Structural Templates for Clinically Validated and Novel Targets in Antimicrobial Drug Research and Development

“…In MRSA, PBP2A can take over the transpeptidase activity and additionally, act as a structural scaffold to recruit acylated PBP2 to the division septum to just exert its essential transglycosylation function (Pinho et al 2001;Pinho and Errington 2005). This PBP2/PBP2A cooperation leads to the formation of peptidoglycan strands with low level of crosslinking (Leski and Tomasz 2005;Atilano et al 2010), which are substrates for PBP4, a secondary transpeptidase that catalyzes the formation of highly crosslinked peptidoglycan (Wyke et al 1981;Atilano et al 2010). It has been demonstrated that the correct localization of PBP4 at the division septum, which is crucial for the resistance mechanism, depends on the presence of wall teichoic acid (WTA) polymers (Scheme 10) (Atilano et al 2010;Brown et al 2012).…”

“…This PBP2/PBP2A cooperation leads to the formation of peptidoglycan strands with low level of crosslinking (Leski and Tomasz 2005;Atilano et al 2010), which are substrates for PBP4, a secondary transpeptidase that catalyzes the formation of highly crosslinked peptidoglycan (Wyke et al 1981;Atilano et al 2010). It has been demonstrated that the correct localization of PBP4 at the division septum, which is crucial for the resistance mechanism, depends on the presence of wall teichoic acid (WTA) polymers (Scheme 10) (Atilano et al 2010;Brown et al 2012). As WTAs are also responsible for the anchoring of autolysins of the peptidoglycan as discussed above, simultaneous inhibition of WTA du i g the p ese e of β-lactams leads to depleted levels of cross-linked peptidoglycan and to non-viable bacteria, thus circumventing the esista e e ha is to a ds β-lactams and restoring their antibacterial activity against Gram-positive bacteria (Maki et al 1994;Swoboda et al 2011;Farha et al 2013;Wang et al 2013;Sewell and Brown 2014;Lee et al 2016a).…”