Hussein Maytham, Wong Labell J M, Zhao Jinxin, Rees Vanessa E, Allobawi Rafah, Sharma Rajnikant, Rao Gauri G, Baker Mark, Li Jian, Velkov Tony
Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3010, Australia.
Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia.
Comput Struct Biotechnol J. 2022 Feb 25;20:1077-1087. doi: 10.1016/j.csbj.2022.02.021. eCollection 2022.
is an opportunistic Gram-negative pathogen causing nosocomial infections. rapidly acquires antibiotic resistance and is known as a reservoir for resistance genes. Polymyxins remain effective as a last-line therapy against infections caused by multidrug-resistant (MDR) ; however, resistance to polymyxins emerges rapidly with monotherapy. Synergistic combinations of polymyxins with FDA-approved non-antibiotics are a novel approach to preserve its efficacy whilst minimising the emergence of polymyxin resistance in . This study aimed to investigate the synergistic antibacterial activity of polymyxin B in combination with the anti-fungal caspofungin against . The combination of polymyxin B and caspofungin showed marked synergistic antibacterial killing activity in checkerboard broth microdilution and static time-kill assays at clinically relevant concentrations at early (0.5 and 1 h) and later (4 h) time points. The potential bacterial killing mechanism of the combination was studied against FADDI-KP001 using metabolomics and transcriptomics studies at 0.5, 1 and 4 h. The key pathways involved in the synergistic killing action of the combination were cell wall assembly (peptidoglycan and lipopolysaccharide biosynthesis), central carbon metabolism (glycolysis, pentose phosphate pathway and tricarboxylic acid cycle) and fatty acid biosynthesis. Moreover, the combination inhibited the most common bacterial virulence pathway (phosphotransferase system) as well as the multi-resistant efflux mechanisms, including ATP-binding cassette (ABC) transporter pathway. Overall, this study sheds light on the possibility of a polymyxin-caspofungin combination for the treatment of infections caused by and may help repurpose FDA-approved caspofungin against MDR infections.
是一种引起医院感染的机会性革兰氏阴性病原体。它能迅速获得抗生素耐药性，是耐药基因的储存库。多粘菌素作为针对多重耐药（MDR）引起的感染的最后一线治疗药物仍然有效；然而，单药治疗时对多粘菌素的耐药性会迅速出现。多粘菌素与FDA批准的非抗生素的协同组合是一种新方法，可在保持其疗效的同时，最大限度地减少多粘菌素耐药性在（此处原文缺失相关对象）中的出现。本研究旨在研究多粘菌素B与抗真菌药物卡泊芬净联合对（此处原文缺失相关对象）的协同抗菌活性。在棋盘肉汤微量稀释法和静态时间杀菌试验中，在临床相关浓度的早期（0.5和1小时）和后期（4小时）时间点，多粘菌素B和卡泊芬净的组合显示出显著的协同抗菌杀灭活性。在0.5、1和4小时，使用代谢组学和转录组学研究针对FADDI-KP001研究了该组合潜在的细菌杀灭机制。该组合协同杀灭作用涉及的关键途径是细胞壁组装（肽聚糖和脂多糖生物合成）、中心碳代谢（糖酵解、磷酸戊糖途径和三羧酸循环）和脂肪酸生物合成。此外，该组合抑制了最常见的细菌毒力途径（磷酸转移酶系统）以及多重耐药外排机制，包括ATP结合盒（ABC）转运途径。总体而言，本研究揭示了多粘菌素-卡泊芬净联合用于治疗（此处原文缺失相关对象）引起的感染的可能性，并可能有助于将FDA批准的卡泊芬净重新用于治疗MDR（此处原文缺失相关对象）感染。
