Harmine, an inhibitor of the type III secretion system of Salmonella enterica serovar Typhimurium

Abstract

New therapeutic strategies for clinical <i>Salmonella enterica</i> serovar Typhimurium (<i>S.</i> Typhimurium) infection are urgently needed due to the generation of antibiotic-resistant bacteria. Inhibition of bacterial virulence has been increasingly regarded as a potential and innovative strategy for the development of anti-infection drugs. <i>Salmonella</i> pathogenicity island (SPI)-encoded type III secretion system (T3SS) represents a key virulence factor in <i>S.</i> Typhimurium, and active invasion and replication in host cells is facilitated by the secretion of T3SS effector proteins. In this study, we found that harmine could inhibit T3SS secretion; thus, its potential anti-<i>S</i>. Typhimurium infection activity was elucidated. Harmine inhibits the secretion and expression of T3SS effector proteins and consequently attenuates the <i>S.</i> Typhimurium invasion function of HeLa cells. This inhibition may be implemented by reducing the transcription of pathogenesis-related SPI-1 transcriptional activator genes <i>hilD</i>, <i>hilC</i>, and <i>rtsA</i>. Harmine improves the survival rate and bacterial loads of mice infected with <i>S</i>. Typhimurium. In summary, harmine, an effective T3SS inhibitor, could be a leading compound for the development of treatments for <i>Salmonella</i> infection.