鸟氨酸拟肽类外排泵抑制剂合成及增效抗生素对抗铜绿假单胞菌活性研究

Synthesis of ornithine peptidomimetic efflux pump inhibitors andsynergistic antibiotic activity against Pseudomonas aeruginosa

为解决铜绿假单胞菌(P.aeruginosa)对多类抗生素耐药难题,寻找P.aeruginosa外排泵抑制剂是一条有效途径。本研究以二肽类外排泵抑制剂PAβN为先导物,通过改变天然氨基酸侧链结构,设计合成15个全新的鸟氨酸拟肽类衍生物,评价了其协同单环β-内酰胺类抗生素氨曲南对抗P.aeruginosa活性。其中,化合物12b不仅可增强β-内酰胺类抗生素,包括氨曲南、头孢他啶、美罗培南的抗菌活性,还可显著增强大环内酯类抗生素克拉霉素的抗菌作用,显示出广谱的协同增敏作用。此外,化合物12b还具有良好的安全性。初步机制显示,12b直接靶向外排转运体MexB发挥作用。研究结果为发展一类新型的对抗MDR P.aeruginosa的外排泵抑制剂提供了新先导化合物。

In order to solve the problem of resistance of Pseudomonas aeruginosa to multiple antibiotics,it is an effective way to find inhibitors of P.aeruginosa efflux pump.In this study,15 new ornithine peptidomimetic derivatives were designed and synthesized by changing the side chain structure of natural amino acids with PAβN,a dipeptide efflux pump inhibitor,and their synergic activity with aztreonam,a monocyclicβ-lactam antibiotic,against P.aeruginosa was evaluated.Among them,the representative compound 12b not only enhanced the antibacterial activity ofβ-lactam antibiotics aztreonam,ceftazidime and meropenem,but also significantly enhanced the antibacterial action of macrolide antibiotics clarithromycin,showing a broad-spectrum synergic sensitization effect.In addition,compound 12b also has a good safety.Preliminary mechanisms suggest that 12b works by directly targeting the efflux transporter MexB.These results provide a new lead compound for the development of a new class of efflux pump inhibitors against P.aeruginosa.