Host-driven remodeling of *Staphylococcus aureus* cell envelope alters antibiotic tolerance and immune evasion

Staphylococcus aureus is a leading cause of life-threatening infections globally, often proving difficult to treat despite available antibiotics. The bacterial cell envelope is critical for S. aureus pathogenesis, serving as the primary interface with host tissues and the immune system, and is a key target for many successful antibiotics. A significant knowledge gap exists in understanding how S. aureus adapts its cell envelope to the hostile, nutrient-limited environment encountered during infection, as most current understanding comes from standard laboratory conditions that do not reflect in vivo complexity.

This comprehensive review synthesized increasing evidence on how host-derived stresses profoundly influence the cell envelope of Staphylococcus aureus. It examined studies performed under conditions reflecting the complex environment encountered during infection, contrasting these findings with observations from standard laboratory conditions. The review focused on identifying specific host-associated factors—such as nutrient limitation, antimicrobial peptides, oxidative stress, altered pH, and hypoxia—and their impact on bacterial membrane and cell wall architecture, as well as the functional consequences for pathogenesis.

Host-associated factors, including nutrient limitation, antimicrobial peptides, oxidative stress, altered pH, and hypoxia, drive extensive, non-genetic remodeling of the Staphylococcus aureus cell envelope. These changes affect multiple aspects of the cell envelope, including phospholipid and fatty acid composition, peptidoglycan thickness, teichoic acid abundance and modification, and capsule production. This host-induced remodeling generates a surface architecture markedly different from that observed in vitro.

Importantly, this host-induced cell envelope remodeling has significant functional consequences, altering bacterial antibiotic tolerance and susceptibility to immune killing, as well as interactions with host cells and tissues. Because these adaptations are non-genetic and reversible, they are unlikely to be detected by conventional diagnostic approaches, yet they play a crucial role in treatment failure and persistent infections by enabling enhanced survival within the host.