<i>Staphylococcus aureus</i> phenol-soluble modulins have dispersal and anti-aggregation activity towards corynebacteria

<i>Staphylococcus aureus</i> is a common upper respiratory tract (URT) pathobiont with high carriage rates in the upper airway disease chronic rhinosinusitis (CRS). CRS is associated with increased prevalence and abundance of <i>S. aureus</i>, and <i>S. aureus-</i>secreted toxins are implicated in CRS pathogenesis. Conversely, in CRS disease, the abundance of non-pathogenic commensal species has been observed to decline, leading to microbial dysbiosis that contributes to persistent inflammation. Here, we investigated possible mechanisms <i>S. aureus</i> could employ to outcompete commensal organisms and contribute to establishing the <i>S. aureus-</i>dominant microbiome found in individuals with CRS. We performed a targeted screen to identify <i>S. aureus-</i>secreted factors that affect the growth and aggregation of a URT commensal bacterium, <i>Corynebacterium pseudodiphtheriticum</i>, which is negatively correlated with <i>S. aureus</i> in CRS. <i>S. aureus</i> cell-free conditioned media prevented <i>C. pseudodiphtheriticum</i> aggregation; however, anti-aggregation activity was significantly reduced in <i>S. aureus</i> mutants lacking a functional accessory gene regulator (agr) quorum-sensing system, phenol-soluble modulin (PSM) transporters, and the PSM toxin δ-toxin. Addition of purified recombinant δ-toxin peptide or a related PSM, PSMα3, inhibited <i>C. pseudodiphtheriticum</i> aggregation and induced dispersal of aggregates. Recombinant δ-toxin also reduced <i>C. pseudodiphtheriticum</i> adherence and aggregation on human nasal epithelial cells. PSMs are known to play a role in biofilm structure and remodeling in staphylococci, and here, we demonstrate that PSMs have activity against other bacteria. These results identify a novel mechanism by which <i>S. aureus</i> can disrupt the commensal lifestyle of microbes that inhabit the same upper respiratory niche via secreted PSM toxins.IMPORTANCEIncreased <i>Staphylococcus aureus</i> abundance and microbial dysbiosis are associated with the pathogenesis of chronic rhinosinusitis disease. Here, we show that <i>S. aureus</i> δ-toxin, a secreted phenol-soluble modulin (PSM) toxin, can inhibit the ability of commensal <i>Corynebacterium</i> species to aggregate, adhere to, and grow in association with human nasal epithelial cells. PSMs are known to play a key role in the <i>S. aureus</i> biofilm life cycle, regulating <i>S. aureus</i> biofilm structure and detachment; however, a role for these toxins in modifying biofilm and aggregate structures of other bacteria has not been previously demonstrated. These results suggest a potential mechanism for <i>S. aureus</i> to establish dominance in the upper respiratory tract microbiome in disease through direct antagonism of commensal microbes with PSM toxins.