Staphylococcus aureus produces phenol-soluble modulins (PSMs), which are amphipathic small peptides with lytic activity against mammalian cells. We previously reported that PSMα1-4 stimulate S. aureus colony spreading, the phenomenon of S. aureus colony expansion on the surface of soft agar plates, whereas δ-toxin (Hld, PSMγ) inhibits colonyspreading activity. In this study, we revealed the underlying mechanism of the opposing effects of PSMα1-4 and δ-toxin in S. aureus colony spreading. PSMα1-4 and δ-toxin are abundant on the S. aureus cell surface, and account for 18% and 8.5% of the total amount of PSMα1-4 and δ-toxin, respectively, in S. aureus overnight cultures. Knockout of PSMα1-4 did not affect the amount of cell surface δ-toxin. In contrast, knockout of δ-toxin increased the amount of cell surface PSMα1-4, and decreased the amount of culture supernatant PSMα1-4. The δ-toxin inhibited PSMα3 and PSMα2 binding to the S. aureus cell surface in vitro. A double knockout strain of PSMα1-4 and δ-toxin exhibited decreased colony spreading compared with the parent strain. Expression of cell surface PSMα1-4, but not culture supernatant PSMα1-4, restored the colony-spreading activity of the PSMα1-4/δ-toxin double knockout strain. Expression of δ-toxin on the cell surface or in the culture supernatant did not restore the colony-spreading activity of the PSMα1-4/δ-toxin double knockout strain. These findings suggest that cell surface PSMα1-4 promote S. aureus colony spreading, whereas δ-toxin suppresses colony-spreading activity by inhibiting PSMα1-4 binding to the S. aureus cell surface.
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