The staphylococcal type VII secretion system impacts daptomycin sensitivity through controlling bacterial cell envelope integrity

The Staphylococcus aureus type VII secretion system (T7SS) plays an important role in bacterial virulence during infection. However, T7SS functions during infection and in bacterial physiology are poorly understood. Here, we demonstrate that S. aureus strains lacking the T7SS transporter EssC or effectors, EsxC and EsxA, were highly sensitive to the important last resort drug, daptomycin. T7SS mutants displayed decreased membrane fluidity, altered cell membrane protein localisation, distinct cell surface morphologies, with effects on cell wall synthesis as well as surface charge under normal growth conditions, indicating that the T7SS is critical to cell envelope function. Daptomycin binding was enhanced in the mutants, whose membranes were more permeable when treated with the drug. Furthermore, the lack of EsxC enhanced daptomycin sensitivity during intracellular infection and during murine skin infection. Thus, our data show that the staphylococcal T7SS impacts sensitivity to membrane-acting drugs through modulating membrane integrity, indicating its potential as a drug target. ### Competing Interest Statement The authors have declared no competing interest.