Sphingosine-mediated death of Pseudomonas aeruginosa involves degradation of cardiolipin by the maintenance of outer lipid asymmetry system

Respiratory infections with multiresistant Pseudomonas aeruginosa are a major clinical problem, affecting mainly patients with pre-existing lung diseases such as cystic fibrosis (CF) or chronic obstructive pulmonary disease but also immunocom promised or elderly patients. We have previously shown that sphingosine, which is abundantly present on epithelial cells of the respiratory tract in healthy humans and wild-type mice, but almost undetectable on the surface of epithelial cells of the respiratory tract from CF patients and CF mice, efficiently kills many bacterial species in vitro and in vivo. Here, we show that sphingosine very rapidly induces marked changes in the membrane of P. aeruginosa with a rolling of the membrane followed by destruction of the bacteria. Sphingosine induced a degradation of cardiolipin via the maintenance of lipid asymmetry (Mla) system in P. aeruginosa. Degradation of cardiolipin induced by sphingosine is prevented in P. aeruginosa mutants of MlaY and reduced in mutants of MlaZ and MlaA. Mutants of MlaY and MlaZ were resistant to sphingosine-induced death of P. aeruginosa. In summary, our data indicate that sphingosine induces the death of P. aeruginosa by a persisting degradation of cardiolipin by the Mla system leading to severe membrane changes in bacteria, while leaving mammalian cells, devoid of cardiolipin in their plasma membrane, alive.