Staphylococcus aureus is one of the leading causes of hospital-acquired infections, largely due to its ability to form biofilms, which are protective bacterial communities embedded in a self-produced extracellular matrix that shield cells from antibiotics and immune responses. The first and essential step before biofilm formation is adhesion to host tissues, mediated by a large family of surface proteins known as MSCRAMMs (microbial surface components recognizing adhesive matrix molecules). These adhesins share a conserved architecture in which the A-domains, composed of tandem immunoglobulin-like folds (N2 and N3), directly mediate adhesion through a dock-lock-latch (DLL) mechanism stabilized by a β-strand latch, while the adjacent B-domains are Ig-fold shock absorbers whose stability is reinforced by calcium. Our group has extensively investigated these adhesins and demonstrated that they form the most mechanically stable non-covalent bonds known, with shear resistance an order of magnitude higher than the classical streptavidin-biotin interaction. Here, we show that calcium plays a role in modulating this stability, with direct implications for skin infections, and that the strength of these bonds has evolved over time. Using molecular dynamics simulations, we find that MRSA strains exhibit significantly greater mechanoresilience than MSSA strains, and both far exceed the stability of early 20th-century isolates collected before the widespread adoption of antibiotics. Dynamic network analysis reveals that the mechanism of mechanoactivation is concerted across the A-domains, with more stable strains exhibiting increased rigidity in their allosteric networks. Importantly, these computational predictions are supported by single-molecule experiments from collaborators, confirming that MRSA adhesins are mechanically stronger than those of MSSA. Together, our results establish that S. aureus adhesins are evolving toward higher mechanical stability, highlighting the critical role of mechanical resilience in the persistence and pathogenic success of S. aureus .
Rafael C. Bernardi (Sun,) studied this question.