The role of lipoteichoic acid in Staphylococcus aureus cell wall integrity

In Staphylococcus aureus, lipoteichoic acid (LTA) is crucial for growth, cell division, osmoprotection, and beta-lactam resistance, yet its molecular mechanisms remain unclear. This study reveals that LTA binds to multiple proteins involved in cell wall processes and preserves cell wall integrity by regulating one of the LTA-binding proteins, ScaH. ScaH is a peptidoglycan hydrolase predicted to have N-acetylglucosaminidase and amidase/peptidase activities. LTA inhibits ScaHs enzymatic activities by direct binding and represses scaH transcription by an unknown mechanism. During early growth, LTA is highly expressed and sequesters ScaH at the cell membrane, preventing ScaH activity in the cell wall. However, LTA expression decreases during the late growth phase, leading to ScaH translocation into the cell wall. This reduction in LTA coincides with increased wall teichoic acid (WTA) expression and cleavage of the LTA synthase LtaS. In the LTA-null mutant, ScaH inactivation restored peptidoglycan crosslinking, osmoresistance, and beta-lactam resistance both in vitro and in vivo. These findings suggest that LTA protects the cell wall by suppressing ScaH expression and activity while sequestering it during active growth. Additionally, the reciprocal expression patterns of LTA and WTA indicate an interconnected regulation of teichoic acids in S. aureus, with their roles likely depending on the growth phase. ImportanceStaphylococcus aureus is a significant human pathogen, with LTA playing a crucial role in cell viability, division, and maintaining cell wall integrity. Targeting LTA synthesis holds promise for the development of new therapeutics against S. aureus. Disruption of LTA synthesis leads to phenotypes indicative of compromised cell wall integrity, such as reduced crosslinking, osmosensitivity, and heightened beta-lactam sensitivity, although the precise underlying mechanisms remain unclear. Our research demonstrates that LTA contributes to cell wall integrity by regulating the expression, activity, and translocation of the peptidoglycan hydrolase ScaH. Additionally, LTAs binding to the cell wall synthesis enzymes suggests a role in modulating cell wall integrity through these interactions. These findings significantly advance our understanding of LTAs physiological functions and may serve as a foundation for the development of novel therapeutics targeting S. aureus and other Gram-positive pathogens.