Effective Strategy Targeting Polymyxin-Resistant Gram-Negative Pathogens: Polymyxin B in Combination with the Selective Serotonin Reuptake Inhibitor Sertraline
Effective Strategy Targeting Polymyxin-Resistant Gram-Negative Pathogens: Polymyxin B in Combination with the Selective Serotonin Reuptake Inhibitor Sertraline
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DOI：
10.1021/acsinfecdis.0c00108
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发表时间：
2020-06-12
影响因子：
5.3
通讯作者：
Velkov, Tony
中科院分区：
文献类型：
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作者：
Hussein, Maytham;Schneider-Futschik, Elena K.;Velkov, Tony
本研究旨在研究多粘菌素B与选择性5-羟色胺再摄取抑制剂舍曲林联合对革兰氏阴性病原体鲍曼不动杆菌、肺炎克雷伯菌和铜绿假单胞菌的协同抗菌活性。多粘菌素B和舍曲林的组合在棋盘和静态时间杀灭试验中在临床相关浓度下对多粘菌素敏感和多粘菌素耐药分离株显示出协同抗菌活性。使用非靶向代谢组学以及扫描和透射电子显微镜（EM）研究了该组合对铜绿假单胞菌FADDI-PA 024的潜在抗菌作用模式。扫描和透射电镜显示，多粘菌素B和舍曲林的组合导致更大的损害，细菌细胞相比，每种药物单独。代谢组学结果表明，该组合显着影响细菌重塑其外膜的能力。这反映在甘油磷脂和脂肪酸以及泛酸和辅酶A（CoA）途径的主要扰动上，其供给脂肪酸延长（例如，反式-十六碳-2-烯酰-CoA）以及抑制脂多糖和肽聚糖的生物合成。该组合还抑制多粘菌素抗性磷酸乙醇胺（pEtN）脂质A修饰途径，这由磷酸乙醇胺水平的下降指示。总之，本研究强调了多粘菌素-舍曲林组合通过直接脑室内/鞘内递送治疗由多重耐药革兰氏阴性菌引起的感染如中枢神经系统（CNS）感染的潜在可能性。
This study aimed to investigate synergistic antibacterial activity of polymyxin B in combination with the selective serotonin reuptake inhibitor, sertraline, against the Gram-negative pathogens Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The combination of polymyxin B and sertraline showed synergistic antibacterial activity in checkerboard and static time-kill assays at clinically relevant concentrations against both polymyxin-susceptible and polymyxin-resistant isolates. The potential antimicrobial mode of action of the combination was investigated against P. aeruginosa FADDI-PA024 using untargeted metabolomics alongside scanning and transmission electron microscopy (EM). Scanning and transmission EM revealed that the polymyxin B and sertraline combination resulted in greater damage to the bacterial cell compared to each drug alone. Metabolomics results showed that the combination significantly affected the bacterial ability to remodel its outer membrane. This was reflected by the major perturbation of glycerophospholipids and fatty acids and the pantothenate and coenzyme A (CoA) pathways, which feed fatty acid elongation (e.g., trans-hexadec-2-enoyl-CoA) as well as inhibit the biosynthesis of lipopolysaccharide and peptidoglycan. The combination also inhibited the polymyxin resistance phosphoethanolamine (pEtN) lipid A modification pathway, indicated by the declined levels of phosphoethanolamine. In summary, the present study highlights the potential possibilities of a polymyxin-sertraline combination for the treatment of infections caused by multidrug resistant Gram-negative bacteria such as central nervous system (CNS) infections via direct intraventricular/intrathecal delivery.