Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia.
ACS Infect Dis. 2021 Jun 11;7(6):1584-1595. doi: 10.1021/acsinfecdis.0c00661. Epub 2021 Apr 9.
Carbapenem-resistant has been classified as an Urgent Threat by the Centers for Disease Control and Prevention (CDC). The combination of two "old" antibiotics, polymyxin and chloramphenicol, displays synergistic killing against New Delhi metallo-β-lactamase (NDM)-producing . However, the mechanism(s) underpinning their synergistic killing are not well studied. We employed an pharmacokinetic/pharmacodynamic model to mimic the pharmacokinetics of the antibiotics in patients and examined bacterial killing against NDM-producing using a metabolomic approach. Metabolomic analysis was integrated with an isolate-specific genome-scale metabolic network (GSMN). Our results show that metabolic responses to polymyxin B and/or chloramphenicol against NDM-producing involved the inhibition of cell envelope biogenesis, metabolism of arginine and nucleotides, glycolysis, and pentose phosphate pathways. Our metabolomic and GSMN modeling results highlight the novel mechanisms of a synergistic antibiotic combination at the network level and may have a significant potential in developing precision antimicrobial chemotherapy in patients.
碳青霉烯类耐药菌已被疾病控制与预防中心（CDC）列为紧急威胁。两种“老”抗生素，多黏菌素和氯霉素的联合使用对产生新德里金属β-内酰胺酶（NDM）的具有协同杀菌作用。然而，它们协同杀菌的机制尚未得到很好的研究。我们采用药代动力学/药效动力学模型来模拟抗生素在患者体内的药代动力学，并采用代谢组学方法研究了针对产生 NDM 的细菌的杀菌作用。代谢组学分析与特定于分离株的基因组规模代谢网络（GSMN）相结合。我们的结果表明，针对产生 NDM 的多黏菌素 B 和/或氯霉素的代谢反应涉及细胞膜生物发生、精氨酸和核苷酸代谢、糖酵解和戊糖磷酸途径的抑制。我们的代谢组学和 GSMN 建模结果突出了协同抗生素组合在网络水平上的新机制，并且在开发针对患者的精准抗菌化疗方面具有重要潜力。
