Synthesis of ornithine peptidomimetic efflux pump inhibitors and synergistic antibiotic activity against Pseudomonas aeruginosa
10.16438/j.0513-4870.2024-0104
- VernacularTitle: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
- Author:
Xi ZHU
;
Xi-can MA
;
Xin-tong ZHANG
;
Yi-shuang LIU
;
Ning HE
;
Yun-ying XIE
;
Dan-qing SONG
- Publication Type:Research Article
- Keywords:
efflux pump inhibitor;
synthesis;
italic>Pseudomonas aeruginosa;
synergistic activity;
MexAB-OprM
- From:
Acta Pharmaceutica Sinica
2024;59(6):1720-1729
- CountryChina
- Language:Chinese
-
Abstract:
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 monocyclic β-lactam antibiotic, against P. aeruginosa was evaluated. Among them, the representative compound 12b not only enhanced the antibacterial activity of β-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.
