Geng Xiang, Zhang Zhen-Dong, Li Yu-Xi, Hao Ruo-Chen, Yang Ya-Jun, Liu Xi-Wang, Li Jian-Yong
Key Lab of New Animal Drug of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou, China.
Front Microbiol. 2024 May 30;15:1396663. doi: 10.3389/fmicb.2024.1396663. eCollection 2024.
() infection and the rapid spread of multi-drug resistant (MDR) bacteria pose a serious threat to global healthcare. Polymyxin E (colistin), a group of cationic antimicrobial polypeptides, is currently one of the last resort treatment options against carbapenem-resistant Gram-negative pathogens. The effectiveness of colistin has been compromised due to its intensive use. This study found that fingolimod (FLD), a natural product derivative, exhibited a significant synergistic bactericidal effect on when combined with colistin, both and . The checkerboard method was employed to assess the synergistic effect of FLD with colistin. FLD enhanced the susceptibility of bacteria to colistin and lowered effectively minimum inhibitory concentrations (MIC) when compared to colistin MIC, and the fractional inhibitory concentrations (FIC) value was less than 0.3. The time-kill curve demonstrated that the combination treatment of FLD and colistin had significant bactericidal efficacy. The concurrent administration of colistin and FLD resulted in heightening membrane permeability, compromising cell integrity, diminishing membrane fluidity, and perturbing membrane homeostasis. They also induced alterations in membrane potential, levels of reactive oxygen species, and adenosine triphosphate synthesis, ultimately culminating in bacterial death. Moreover, the combination of FLD with colistin significantly influenced fatty acid metabolism. In the mouse infection model, the survival rate of mice injected with was significantly improved to 67% and pathological damage was significantly relieved with combination treatment of FLD and colistin when compared with colistin treatment. This study highlights the potential of FLD in combining with colistin for treating infections caused by MDR isolates of .
（）感染以及多重耐药（MDR）细菌的迅速传播对全球医疗保健构成严重威胁。多粘菌素E（黏菌素）是一组阳离子抗菌多肽，目前是对抗碳青霉烯耐药革兰氏阴性病原体的最后治疗选择之一。由于黏菌素的大量使用，其有效性已受到损害。本研究发现，天然产物衍生物芬戈莫德（FLD）与黏菌素联合使用时，对[具体细菌]表现出显著的协同杀菌作用，无论是[细菌种类1]还是[细菌种类2]。采用棋盘法评估FLD与黏菌素的协同作用。与黏菌素的最低抑菌浓度（MIC）相比，FLD增强了细菌对黏菌素的敏感性并有效降低了MIC，且分数抑菌浓度（FIC）值小于0.3。时间 - 杀菌曲线表明，FLD与黏菌素联合治疗具有显著的杀菌效果。同时给予黏菌素和FLD导致膜通透性增加、细胞完整性受损、膜流动性降低以及膜稳态紊乱。它们还诱导膜电位、活性氧水平和三磷酸腺苷合成发生变化，最终导致细菌死亡。此外，FLD与黏菌素的组合显著影响脂肪酸代谢。在小鼠感染模型中，与黏菌素治疗相比，联合使用FLD和黏菌素治疗时，注射[具体细菌]的小鼠存活率显著提高至67%，病理损伤也显著减轻。本研究突出了FLD与黏菌素联合治疗由[具体细菌]的MDR分离株引起的感染的潜力。
