The rapid prevalence of antibiotic resistance has led to a significant global health problem. Although colistin is the last resort antibiotic, it is limited by dose dependent toxicity. A critical approach to solve thi...The rapid prevalence of antibiotic resistance has led to a significant global health problem. Although colistin is the last resort antibiotic, it is limited by dose dependent toxicity. A critical approach to solve this problem is to use an antibiotic adjuvant, which is able to potentiate the activity of antibiotic and reduce the dosage of antibiotic. Herein, we reported a novel 2-aminothiazoyl piperidine adjuvant, which enhanced the activity of colistin against Acinetobacter baumannii(A. baumannii). Two pilot libraries of 40compounds were prepared and their adjuvant activities were evaluated. The most potential compound11j enabled to cause16-fold reduction in the minimum inhibitory concentration(MIC) of colistin at 8μg/m L. Besides, time-kill curves exhibited that compound 11j had significant adjuvant activity to kill the bacteria. The predicted ADMET analysis showed that 2-aminothiazoyl piperidine derivatives had good drug-likeness and acceptable physicochemical properties. Furthermore, membrane permeability experiments demonstrated that compound 11j was beneficial for colistin to destroy the outer membrane of bacteria. Also, the comparative molecular similarity indices analysis(Co MSIA) and the density functional theory(DFT) calculations were conducted. The results drawn from these analyses indicated that the novel scaffold provided helpful information for the finding of new adjuvant lead.展开更多
基金financially supported by the National Natural Science Foundation of China (No. 81872775)。
文摘The rapid prevalence of antibiotic resistance has led to a significant global health problem. Although colistin is the last resort antibiotic, it is limited by dose dependent toxicity. A critical approach to solve this problem is to use an antibiotic adjuvant, which is able to potentiate the activity of antibiotic and reduce the dosage of antibiotic. Herein, we reported a novel 2-aminothiazoyl piperidine adjuvant, which enhanced the activity of colistin against Acinetobacter baumannii(A. baumannii). Two pilot libraries of 40compounds were prepared and their adjuvant activities were evaluated. The most potential compound11j enabled to cause16-fold reduction in the minimum inhibitory concentration(MIC) of colistin at 8μg/m L. Besides, time-kill curves exhibited that compound 11j had significant adjuvant activity to kill the bacteria. The predicted ADMET analysis showed that 2-aminothiazoyl piperidine derivatives had good drug-likeness and acceptable physicochemical properties. Furthermore, membrane permeability experiments demonstrated that compound 11j was beneficial for colistin to destroy the outer membrane of bacteria. Also, the comparative molecular similarity indices analysis(Co MSIA) and the density functional theory(DFT) calculations were conducted. The results drawn from these analyses indicated that the novel scaffold provided helpful information for the finding of new adjuvant lead.
