Deciphering molecular mechanism of silver by integrated omic approaches enables enhancing its antimicrobial efficacy in E. coli

doi:10.1371/journal.pbio.3000292

	Deciphering molecular mechanism of silver by integrated omic approaches enables enhancing its antimicrobial efficacy in E. coli
	Wang, Haibo 4; Yan, Aixin 5; Liu, Zhigang 6; Yang, Xinming 4; Xu, Zeling 5; Wang, Yuchuan 7; Wang, Runming 4; Koohi-Moghadam, Mohamad 4; Hu, Ligang 8; Xia, Wei 7
刊名	PLOS BIOLOGY
	2019-06-01
卷号	17 期号:6 页码:31
ISSN号	1544-9173
DOI	10.1371/journal.pbio.3000292
英文摘要	Despite the broad-spectrum antimicrobial activities of silver, its internal usage is restricted, owing to the toxicity. Strategies to enhance its efficacy are highly desirable but rely heavily on the understanding of its molecular mechanism of action. However, up to now, no direct silver-targeting proteins have been mined at a proteome-wide scale, which hinders systemic studies on the biological pathways interrupted by silver. Herein, we build up a unique system, namely liquid chromatography gel electrophoresis inductively coupled plasma mass spectrometry (LC-GE-ICP-MS), allowing 34 proteins directly bound by silver ions to be identified in Escherichia coli. By using integrated omic approaches, including metalloproteomics, metabolomics, bioinformatics, and systemic biology, we delineated the first dynamic antimicrobial actions of silver (Ag+) in E. coli, i.e., it primarily damages multiple enzymes in glycolysis and tricarboxylic acid (TCA) cycle, leading to the stalling of the oxidative branch of the TCA cycle and an adaptive metabolic divergence to the reductive glyoxylate pathway. It then further damages the adaptive glyoxylate pathway and suppresses the cellular oxidative stress responses, causing systemic damages and death of the bacterium. To harness these novel findings, we coadministrated metabolites involved in the Krebs cycles with Ag+ and found that they can significantly potentiate the efficacy of silver both in vitro and in an animal model. Our study reveals the comprehensive and dynamic mechanisms of Ag+ toxicity in E. coli cells and offers a novel and general approach for deciphering molecular mechanisms of metallodrugs in various pathogens and cells to facilitate the development of new therapeutics.
资助项目	Research Grants Council of Hong Kong[17305415] ; Research Grants Council of Hong Kong[1733616] ; Research Grants Council of Hong Kong[17307017] ; National Science Foundation of China[21671203] ; University of Hong Kong ; Hong Kong PhD Fellowship (HKPF)
WOS关键词	ESCHERICHIA-COLI ; ANTIBACTERIAL ACTION ; GEL-ELECTROPHORESIS ; RESPIRATORY-CHAIN ; PROTEINS ; BINDING ; CELLS ; ION ; IDENTIFICATION ; NANOPARTICLES
WOS研究方向	Biochemistry & Molecular Biology ; Life Sciences & Biomedicine - Other Topics
语种	英语
出版者	PUBLIC LIBRARY SCIENCE
WOS记录号	WOS:000473675900017
资助机构	Research Grants Council of Hong Kong ; Research Grants Council of Hong Kong ; National Science Foundation of China ; National Science Foundation of China ; University of Hong Kong ; University of Hong Kong ; Hong Kong PhD Fellowship (HKPF) ; Hong Kong PhD Fellowship (HKPF) ; Research Grants Council of Hong Kong ; Research Grants Council of Hong Kong ; National Science Foundation of China ; National Science Foundation of China ; University of Hong Kong ; University of Hong Kong ; Hong Kong PhD Fellowship (HKPF) ; Hong Kong PhD Fellowship (HKPF) ; Research Grants Council of Hong Kong ; Research Grants Council of Hong Kong ; National Science Foundation of China ; National Science Foundation of China ; University of Hong Kong ; University of Hong Kong ; Hong Kong PhD Fellowship (HKPF) ; Hong Kong PhD Fellowship (HKPF) ; Research Grants Council of Hong Kong ; Research Grants Council of Hong Kong ; National Science Foundation of China ; National Science Foundation of China ; University of Hong Kong ; University of Hong Kong ; Hong Kong PhD Fellowship (HKPF) ; Hong Kong PhD Fellowship (HKPF)
内容类型	期刊论文
源URL	[http://ir.wipm.ac.cn/handle/112942/14630]
专题	中国科学院武汉物理与数学研究所
通讯作者	Sun, Hongzhe
作者单位	1.Zhongshan Hosp, State Key Lab Genet Engn, Shanghai, Peoples R China 2.Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore Phenome Ctr, Singapore, Singapore 3.Fudan Univ, Sch Life Sci, Shanghai Int Ctr Mol Phen, Collaborat Innovat Ctr Genet & Dev, Shanghai, Peoples R China 4.Univ Hong Kong, Dept Chem, Hong Kong, Peoples R China 5.Univ Hong Kong, Sch Biol Sci, Hong Kong, Peoples R China 6.Chinese Acad Sci, Natl Ctr Magnet Resonance Wuhan, State Key Lab Magnet Resonance & Atom & Mol Phys, Wuhan Inst Phys & Math,CAS Key Lab Magnet Resonan, Wuhan, Hubei, Peoples R China 7.Sun Yat Sen Univ, Sch Chem, Guangzhou, Guangdong, Peoples R China 8.Chinese Acad Sci, Res Ctr Ecoenvironm Sci, State Key Lab Environm Chem & Ecotoxicol, Beijing, Peoples R China
推荐引用方式 GB/T 7714	Wang, Haibo,Yan, Aixin,Liu, Zhigang,et al. Deciphering molecular mechanism of silver by integrated omic approaches enables enhancing its antimicrobial efficacy in E. coli[J]. PLOS BIOLOGY,2019,17(6):31.
APA	Wang, Haibo.,Yan, Aixin.,Liu, Zhigang.,Yang, Xinming.,Xu, Zeling.,...&Sun, Hongzhe.(2019).Deciphering molecular mechanism of silver by integrated omic approaches enables enhancing its antimicrobial efficacy in E. coli.PLOS BIOLOGY,17(6),31.
MLA	Wang, Haibo,et al."Deciphering molecular mechanism of silver by integrated omic approaches enables enhancing its antimicrobial efficacy in E. coli".PLOS BIOLOGY 17.6(2019):31.