Guangzhou Key Laboratory of Enhanced Recovery After Abdominal Surgery, Department of Clinical Laboratory, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Kunming Key Laboratory of Children Infection and Immunity, Yunnan Institute of Pediatrics, Kunming Children's Hospital, Kunming, China.
Microb Drug Resist. 2022 Jan;28(1):7-17. doi: 10.1089/mdr.2020.0511. Epub 2021 Aug 3.
is an opportunistic pathogen, which usually presents multiple antibiotic resistance. Host-directed therapy involves modulating the host defense system and the interplay between innate and adaptive immunity is a new strategy for designing anti-infection drugs. Memantine (MEM), a drug used to treat Alzheimer's disease, has a good inhibitory effect on neonatal mice with -associated bacteremia and meningitis; however, the inhibitory effect and mechanisms of MEM against infection remain unclear. Here, we investigated whether MEM could inhibit infection and explored the potential mechanisms. MEM significantly promoted the bactericidal effect of neutrophils against and its drug-resistant strain. The combination index of MEM and amikacin (AMK) was <1. experiments showed that the bacteremia and inflammation severities in the MEM-treated group were less than those in the untreated group, and the bacterial load in the organs was significantly less than that in the control group. Combining MEM with the reactive oxygen species (ROS) inhibitor, -acetyl-l-cysteine, weakened the anti-infective effect of MEM. MEM increased the expression of NADPH p67phox and promoted neutrophilic ROS production. Deleting the p67phox gene significantly weakened the effects of MEM on ROS generation and improving bactericidal effect of neutrophils. In conclusion, MEM promoted the bactericidal effect of neutrophils against and its drug-resistant strain, and had a synergistic antibacterial effect when combined with AMK. MEM may exert its anti-infective effects by promoting neutrophilic bactericidal activity via increasing the expression level of p67phox and further stimulating ROS generation.
是一种机会性病原体，通常表现出多种抗生素耐药性。宿主导向治疗涉及调节宿主防御系统，固有免疫和适应性免疫之间的相互作用是设计抗感染药物的新策略。用于治疗老年痴呆症的药物美金刚（MEM）对伴有菌血症和脑膜炎的新生鼠有很好的抑制作用；然而，MEM 对感染的抑制作用及其机制尚不清楚。在这里，我们研究了 MEM 是否可以抑制感染，并探讨了其潜在机制。MEM 显著促进了中性粒细胞对和其耐药株的杀菌作用。MEM 和阿米卡星（AMK）的组合指数<1。实验表明，MEM 处理组的菌血症和炎症严重程度低于未处理组，且器官中的细菌负荷明显低于对照组。将 MEM 与活性氧（ROS）抑制剂乙酰半胱氨酸联合使用，削弱了 MEM 的抗感染作用。MEM 增加了 NADPH p67phox 的表达，并促进了中性粒细胞的 ROS 产生。删除 p67phox 基因显著减弱了 MEM 对 ROS 生成和提高中性粒细胞杀菌作用的影响。综上所述，MEM 促进了中性粒细胞对和其耐药株的杀菌作用，与 AMK 联合使用具有协同抗菌作用。MEM 可能通过增加 p67phox 的表达水平并进一步刺激 ROS 生成来发挥其抗感染作用。
