Synergistic effect of β-thujaplicin and tigecycline against tet(X4)-positive Escherichia coli in vitro.

Muchen Zhang; Huangwei Song; Zhiyu Zou; Siyuan Yang; Hui LI; Chongshan Dai; Dejun Liu; Bing Shao; Congming WU; Jianzhong Shen; Yang Wang

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Synergistic effect of β-thujaplicin and tigecycline against tet(X4)-positive Escherichia coli in vitro.

Author: Muchen ZHANG ¹ ; Huangwei SONG ¹ ; Zhiyu ZOU ¹ ; Siyuan YANG ¹ ; Hui LI ² ; Chongshan DAI ¹ ; Dejun LIU ¹ ; Bing SHAO ² ; Congming WU ¹ ; Jianzhong SHEN ¹ ; Yang WANG ¹
Author Information

1. Key Laboratory of Animal Antimicrobial Resistance Surveillance, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
2. Beijing Center for Disease Prevention and Control, Beijing 100013, China.
Publication Type:Journal Article
Keywords: iron homeostasis; synergistic antibacterial effect; tet(X4); tigecycline; β-thujaplicin
MeSH: Humans; Tigecycline/pharmacology*; Escherichia coli/metabolism*; Reactive Oxygen Species/therapeutic use*; Plasmids; Anti-Bacterial Agents/metabolism*; Escherichia coli Infections/microbiology*; Bacteria/genetics*; Microbial Sensitivity Tests
From: Chinese Journal of Biotechnology 2023;39(4):1621-1632
CountryChina
Language:Chinese
Abstract: The widespread of tigecycline resistance gene tet(X4) has a serious impact on the clinical efficacy of tigecycline. The development of effective antibiotic adjuvants to combat the looming tigecycline resistance is needed. The synergistic activity between the natural compound β-thujaplicin and tigecycline in vitro was determined by the checkerboard broth microdilution assay and time-dependent killing curve. The mechanism underlining the synergistic effect between β-thujaplicin and tigecycline against tet(X4)-positive Escherichia coli was investigated by determining cell membrane permeability, bacterial intracellular reactive oxygen species (ROS) content, iron content, and tigecycline content. β-thujaplicin exhibited potentiation effect on tigecycline against tet(X4)-positive E. coli in vitro, and presented no significant hemolysis and cytotoxicity within the range of antibacterial concentrations. Mechanistic studies demonstrated that β-thujaplicin significantly increased the permeability of bacterial cell membranes, chelated bacterial intracellular iron, disrupted the iron homeostasis and significantly increased intracellular ROS level. The synergistic effect of β-thujaplicin and tigecycline was identified to be related to interfere with bacterial iron metabolism and facilitate bacterial cell membrane permeability. Our studies provided theoretical and practical data for the application of combined β-thujaplicin with tigecycline in the treatment of tet(X4)-positive E. coli infection.