Zhang Yi, Han Yijia, Wang Lingbo, Kong Jingchun, Pan Wei, Zhang Xiaodong, Chen Lijiang, Yao Zhuocheng, Zhou Tieli, Cao Jianming
Department of Medical Lab Science, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Wenzhou, Zhejiang Province, China.
Microbiol Spectr. 2023 Mar 27;11(2):e0405222. doi: 10.1128/spectrum.04052-22.
The continuous development of multidrug-resistant (MDR) Gram-negative bacteria poses a serious risk to public health on a worldwide scale. Colistin is used as the last-line antibiotic for the treatment of MDR pathogens, and colistin-resistant (COL-R) bacterial emergence thus has the potential to have a severe adverse impact on patient outcomes. In this study, synergistic activity was observed when colistin and flufenamic acid (FFA) were combined and used for the treatment of clinical COL-R Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii strains, as shown by checkerboard and time-kill assays. Crystal violet staining and scanning electron microscopy revealed the synergistic action of colistin-FFA against biofilms. When used to treat murine RAW264.7 macrophages, this combination did not induce any adverse toxicity. Strikingly, the survival rates of bacterially infected Galleria mellonella larvae were improved by such combination treatment, which was also sufficient to reduce the measured bacterial loads in a murine thigh infection model. Mechanistic propidium iodide (PI) staining analysis further demonstrated the ability of these agents to alter bacterial permeability in a manner that enhanced the efficacy of colistin treatment. Together, these data thus demonstrate that colistin and FFA can be synergistically combined to combat the spread of COL-R Gram-negative bacteria, providing a promising therapeutic tool with the potential to protect against COL-R bacterial infections and improve patient outcomes. Colistin is a last-line antibiotic used for the treatment of MDR Gram-negative bacterial infections. However, increasing resistance to it has been observed during clinical treatment. In this work, we assessed the efficacy of the combination of colistin and FFA for the treatment of COL-R bacterial isolates, demonstrating that the combined treatment has effective antibacterial and antibiofilm activities. Due to its low cytotoxicity and good therapeutic effects , the colistin-FFA combination may be a potential candidate for research into a resistance-modifying agent to combat infections caused by COL-R Gram-negative bacteria.
多重耐药（MDR）革兰氏阴性菌的不断发展在全球范围内对公众健康构成严重风险。黏菌素被用作治疗MDR病原体的最后一线抗生素，因此耐黏菌素（COL-R）细菌的出现有可能对患者的治疗结果产生严重的不利影响。在本研究中，棋盘法和时间杀菌试验表明，当黏菌素与氟芬那酸（FFA）联合用于治疗临床COL-R铜绿假单胞菌、大肠杆菌、肺炎克雷伯菌和鲍曼不动杆菌菌株时，观察到了协同活性。结晶紫染色和扫描电子显微镜显示了黏菌素-FFA对生物膜的协同作用。当用于治疗小鼠RAW264.7巨噬细胞时，这种组合不会诱导任何不良毒性。引人注目的是，这种联合治疗提高了感染细菌的大蜡螟幼虫的存活率，这也足以降低小鼠大腿感染模型中测得的细菌载量。机制碘化丙啶（PI）染色分析进一步证明了这些药物能够以增强黏菌素治疗效果的方式改变细菌通透性。总之，这些数据表明，黏菌素和FFA可以协同联合起来对抗COL-R革兰氏阴性菌的传播，提供了一种有前景的治疗工具，有可能预防COL-R细菌感染并改善患者治疗结果。黏菌素是用于治疗MDR革兰氏阴性菌感染的最后一线抗生素。然而，在临床治疗过程中已观察到对其耐药性的增加。在这项工作中，我们评估了黏菌素和FFA联合治疗COL-R细菌分离株的疗效，证明联合治疗具有有效的抗菌和抗生物膜活性。由于其低细胞毒性和良好的治疗效果，黏菌素-FFA组合可能是研究用于对抗COL-R革兰氏阴性菌引起的感染的耐药性修饰剂的潜在候选物。
