VraH Is the Third Component of the Staphylococcus aureus VraDEH System Involved in Gallidermin and Daptomycin Resistance and Pathogenicity

In bacteria, extracellular signals are transduced into the cell predominantly by two-component systems (TCSs) comprising a regulatory unit triggered by a specific signal. Some of the TCSs control executing units such as ABC transporters involved in antibiotic resistance. For instance, in Staphylococcus aureus, activation of BraSR leads to the upregulation of vraDE expression that encodes an ABC transporter playing a role in bacitracin and nisin resistance. In this study, we show that the small staphylococcal transmembrane protein VraH forms, together with VraDE, a three-component system. Although the expression of vraH in the absence of vraDE was sufficient to mediate low-level resistance, only this VraDEH entity conferred high-level resistance against daptomycin and gallidermin. In most staphylococcal genomes, vraH is located immediately downstream of vraDE, forming an operon, whereas in some species it is localized differently. In an invertebrate infection model, VraDEH significantly enhanced S. aureus pathogenicity. In analogy to the TCS connectors, VraH can be regarded as an ABC connector that modulates the activity of ABC transporters involved in antibiotic resistance.