Abstract：
OBJECTIVE: Aztreonam/avibactam is effective against serious infections caused by Gram-negative bacteria including Enterobacterales harboring metallo-β-lactamases. While the utility of this combination has been established in vitro and in clinical trials, the purpose of this study is to enhance our understanding of the underlying mechanism responsible for their activities through metabolomic profiling of a multidrug-resistant Escherichia coli clinical isolate.
METHODS: Metabolomic analyses of time-dependent changes in endogenous bacterial metabolites in a clinical isolate of a multidrug-resistant E. coli treated with aztreonam and avibactam were performed. E. coli metabolomes were compared at 15 min, 1 h and 24 h following treatments with either avibactam (4 mg/L), aztreonam (4 mg/L), or aztreonam (4 mg/L) + avibactam (4 mg/L).
RESULTS: Drug treatment affected 326 metabolites with magnitude changes of at least 2-fold, most of which are involved primarily in peptidoglycan biosynthesis, nucleotide metabolism, and lipid metabolism. The feedstocks for peptidoglycan synthesis were depleted by aztreonam/avibactam combination; a significant downstream increase in nucleotide metabolites and a release of lipids were observed at the three timepoints.
CONCLUSIONS: The findings indicate that the aztreonam/avibactam combination accelerates structural damage to the bacterial membrane structure and their actions were immediate and sustained compared to aztreonam or avibactam alone. By inhibiting the production of crucial cell wall precursors, the combination may have inflicted damages on bacterial DNA.
METHODS: Metabolomic analyses of time-dependent changes in endogenous bacterial metabolites in a clinical isolate of a multidrug-resistant E. coli treated with aztreonam and avibactam were performed. E. coli metabolomes were compared at 15 min, 1 h and 24 h following treatments with either avibactam (4 mg/L), aztreonam (4 mg/L), or aztreonam (4 mg/L) + avibactam (4 mg/L).
RESULTS: Drug treatment affected 326 metabolites with magnitude changes of at least 2-fold, most of which are involved primarily in peptidoglycan biosynthesis, nucleotide metabolism, and lipid metabolism. The feedstocks for peptidoglycan synthesis were depleted by aztreonam/avibactam combination; a significant downstream increase in nucleotide metabolites and a release of lipids were observed at the three timepoints.
CONCLUSIONS: The findings indicate that the aztreonam/avibactam combination accelerates structural damage to the bacterial membrane structure and their actions were immediate and sustained compared to aztreonam or avibactam alone. By inhibiting the production of crucial cell wall precursors, the combination may have inflicted damages on bacterial DNA.
摘要：
目的：氨曲南/阿维巴坦对革兰氏阴性菌包括含有金属β-内酰胺酶的肠杆菌引起的严重感染有效。虽然这种组合的效用已经在体外和临床试验中确立，这项研究的目的是通过对多重耐药大肠杆菌临床分离株进行代谢组学分析，加深我们对其活性的潜在机制的理解。
方法：对用氨曲南和阿维巴坦处理的多药耐药大肠杆菌临床分离株内源性细菌代谢产物的时间依赖性变化进行了代谢组学分析。大肠杆菌代谢组在15分钟时进行比较，使用阿维巴坦（4mg/L）治疗后1小时和24小时，氨曲南（4毫克/升），或氨曲南（4mg/L）+阿维巴坦（4mg/L）。
结果：药物治疗影响了326种代谢物，其幅度变化至少为2倍，其中大多数主要参与肽聚糖的生物合成，核苷酸代谢，和脂质代谢。通过氨曲南/阿维巴坦组合耗尽肽聚糖合成的原料;在三个时间点观察到核苷酸代谢物的显著下游增加和脂质的释放。
结论：研究结果表明，与单独使用氨曲南或阿维巴坦相比，氨曲南/阿维巴坦组合可加速细菌膜结构的结构损伤，其作用是直接和持续的。通过抑制关键细胞壁前体的产生，该组合可能对细菌DNA造成损害。
方法：对用氨曲南和阿维巴坦处理的多药耐药大肠杆菌临床分离株内源性细菌代谢产物的时间依赖性变化进行了代谢组学分析。大肠杆菌代谢组在15分钟时进行比较，使用阿维巴坦（4mg/L）治疗后1小时和24小时，氨曲南（4毫克/升），或氨曲南（4mg/L）+阿维巴坦（4mg/L）。
结果：药物治疗影响了326种代谢物，其幅度变化至少为2倍，其中大多数主要参与肽聚糖的生物合成，核苷酸代谢，和脂质代谢。通过氨曲南/阿维巴坦组合耗尽肽聚糖合成的原料;在三个时间点观察到核苷酸代谢物的显著下游增加和脂质的释放。
结论：研究结果表明，与单独使用氨曲南或阿维巴坦相比，氨曲南/阿维巴坦组合可加速细菌膜结构的结构损伤，其作用是直接和持续的。通过抑制关键细胞壁前体的产生，该组合可能对细菌DNA造成损害。
