Design and characterization of a polyamine derivative inhibiting the expression of type III secretion system in...

The type III secretion system (TTSS) of Pseudomonas aeruginosa is a key virulence determinant for infection of eukaryotic hosts. Based on the findings that spermidine-mediated host-pathogen signalling is important for activation of type III secretion systems (TTSS), in this study, we designed, synthesized and evaluated a series of polyamine derivatives for their potentials in inhibiting the expression TTSS in P. aeruginosa. In vitro assay of 15 compounds synthesized in this study unveiled stringent structural requirements for TTSS-inhibitory activity. Among them, R101SPM, a conjugate between rhodamine 101 and spermine, showed a potent activity in inhibition of the TTSS gene expression and in attenuation of the TTSS-mediated cytotoxicity on human cells. In vivo analysis demonstrated that R101SPM could rescue mice from the lethal infection by P. aeruginosa. Moreover, genetic analysis showed that the full TTSS-inhibitory activity of R101SPM required a functional spermidine transporter. Taken together, our results present a new class of lead molecules for developing anti-virulence drugs and demonstrate that the spermidine transporter SpuDEGHF of P. aeruginosa is a promising drug target.