title: Design and characterization of a polyamine derivative inhibiting the expression of type III secretion system in Pseudomonas aeruginosa.
abstract: 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.
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, 138673, Singapore.|National Cancer Centre Singapore, 11 Hospital Drive, 169610, Singapore.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, 138673, Singapore.|Chongqing Academy of Chinese Materia Medica, 400065, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liu
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, 138673, Singapore.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, 510642, China.
authors.forename: Jianuan
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, 510642, China.
authors.forename: Zining
authors.initials: Z
authors.lastname: Cui
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, 138673, Singapore.|Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, 510642, China.
authors.forename: Lian-Hui
authors.initials: LH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D058947:Bacterial Secretion Systems / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D008297:Male; D051379:Mice; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000378:metabolism* / Q000472:pathogenicity; D012235:Rhodamines / Q000494:pharmacology*; D013095:Spermidine / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D058947:Bacterial Secretion Systems; D012235:Rhodamines; D013095:Spermidine