Host-driven remodelling of the Staphylococcus aureus cell envelope: mechanisms, consequences and therapeutic implications.

Staphylococcus aureus is a leading cause of life-threatening infections worldwide and remains difficult to treat despite the availability of antibiotics. The bacterial cell envelope is central to S. aureus pathogenesis as it forms the primary interface with host tissues and the immune system and is the target for many of our most successful antibiotics. Much of our current understanding of staphylococcal cell envelope biology derives from studies performed under standard laboratory conditions that do not accurately reflect the complex environment encountered during infection. Increasing evidence indicates that S. aureus profoundly remodels its cell envelope in response to host-derived stresses, generating a surface architecture that differs markedly from that observed in vitro. This review discusses how host-associated factors, including nutrient limitation, antimicrobial peptides, oxidative stress, altered pH and hypoxia, drive extensive remodelling of both the bacterial membrane and the cell wall. 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. Importantly, this host-induced cell envelope remodelling has important functional consequences, altering antibiotic tolerance, susceptibility to immune killing and interactions with host cells and tissues. Because these changes are non-genetic and reversible, they are unlikely to be detected by conventional diagnostic approaches; however, they may play an important role in treatment failure and persistent infection.