Sphingosine kills Mycobacteria and suppresses mycobacterial lung infections.

Abstract

Tuberculous mycobacterial infections pose a substantial global health burden because of their prevalence and multi-drug resistance. The current approach to tackling these infections primarily involves developing new antibiotics or combining existing ones, an approach that often proves ineffective in the specific targeting of mycobacteria. We investigated the effect of sphingosine on tuberculous Mycobacteria in vitro and mycobacterial infections in vivo to test whether sphingosine could potentially be used as a novel drug against tuberculosis. Sphingosine inhibited mycobacterial growth and eradicated mycobacteria in vitro. Mechanistically, sphingosine increased bacterial membrane permeability and induced marked changes on the bacterial plasma membrane evidenced by electron microscopy studies. Administration of sphingosine in a mouse model of pulmonary infection with Bacillus Calmette-Guérin (BCG) greatly reduced the number of bacteria in the lung and prevented pulmonary inflammation. Furthermore, infection of ex vivo human lung tissue samples with BCG and treatment with sphingosine showed that sphingosine also kills BCG in human bronchi. Our findings suggest that sphingosine may be a potential therapeutic intervention against mycobacterial infections. KEY MESSAGES: Sphingosine inhibits mycobacterial growth in vitro. Sphingosine disrupts bacterial membrane integrity. Sphingosine reduces bacterial load in mouse pulmonary infection model. Sphingosine eradicates mycobacteria in human bronchi ex vivo.