Wang Chao, Liu Xiaoling, Wang Jing, Zhou Jianuan, Cui Zining, Zhang Lian-Hui
Institute of Molecular and Cell Biology, 61 Biopolis Drive, 138673, Singapore.
National Cancer Centre Singapore, 11 Hospital Drive, 169610, Singapore.
Sci Rep. 2016 Aug 3;6:30949. doi: 10.1038/srep30949.
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.
铜绿假单胞菌的III型分泌系统（TTSS）是其感染真核宿主的关键毒力决定因素。基于亚精胺介导的宿主-病原体信号传导对III型分泌系统（TTSS）激活很重要这一发现，在本研究中，我们设计、合成并评估了一系列多胺衍生物抑制铜绿假单胞菌中TTSS表达的潜力。对本研究中合成的15种化合物进行的体外试验揭示了TTSS抑制活性的严格结构要求。其中，罗丹明101与精胺的共轭物R101SPM在抑制TTSS基因表达以及减弱TTSS介导的对人细胞的细胞毒性方面表现出强大活性。体内分析表明，R101SPM可使小鼠免于铜绿假单胞菌的致死性感染。此外，基因分析表明，R101SPM的完全TTSS抑制活性需要功能性亚精胺转运蛋白。综上所述，我们的结果提出了一类用于开发抗毒力药物的新型先导分子，并证明铜绿假单胞菌的亚精胺转运蛋白SpuDEGHF是一个有前景的药物靶点。
