Sphingosine inhalation as a novel treatment for bacterial pneumonia

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We have previously shown that low micromolar concentrations of sphingosine kill manypathogens, including Pseudomonas aeruginosa, Staphylococcus aureus (even MRSA),Acinetobacter baumannii, Haemophilus influenzae, Moraxella catarrhalis, and Burkholderia species, that are important pathogens in many forms of pneumonia. Administering sphingosine to cystic fibrosis (CF) mice by inhalation prevents infection of these mice with P. aeruginosa or S. aureus. Inhalation of sphingosine by CF mice also eliminates already existing acute or chronic infections with planktonic or biofilm P. aeruginosa or S. aureus.Furthermore, we noticed no toxic effects among mice and minipigs that had inhaledsphingosine twice daily for two weeks. Because an increasing number of multiresistantbacteria cause pneumonia and chronic lung infections, novel strategies for treating bacterial infections are needed. We hypothesize that inhaled sphingosine can be developed into a novel treatment option for patients with bacterial pneumonia or chronic lung infection, in particular CF patients. The present proposal aims (i) to characterize the ability of sphingosine to eliminate P. aeruginosa and S. aureus infection in pigs, in cultured human airway epithelial cells, and in isolated human lungs; and (ii) to determine the potential adverse effects of sphingosine on cultured human epithelial cells, lungs of infected pigs, and isolated uninfected and infected human lungs. Our ultimate aim is to establish the basis for a clinical study testing the antibacterial effects of sphingosine in CF patients.The project combines the expertise of three groups, i.e. E.G. will perform the experiments on pigs in vivo and will provide expertise on sphingolipids, M.K. will perform the studies on perfused and ventilated pigs and human lungs and C.T. will perform all studies on cultured human cells. The project is truly a joint venture and requires the expertise and efforts of all three groups.