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

TitleDeciphering molecular mechanism of silver by integrated omic approaches enables enhancing its antimicrobial efficacy in E. coli
Authors
KeywordsSilver
Glucose metabolism
Metabolites
Citric acid cycle
Cell metabolism
Issue Date2019
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosbiology.org/plosonline/?request=index-html
Citation
PLoS Biology, 2019, v. 17 n. 6, article no. e3000292 How to Cite?
AbstractDespite 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.
Persistent Identifierhttp://hdl.handle.net/10722/280268
ISSN
2019 Impact Factor: 7.076
2015 SCImago Journal Rankings: 5.293
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorWang, H-
dc.contributor.authorYan, A-
dc.contributor.authorLiu, Z-
dc.contributor.authorYang, X-
dc.contributor.authorXu, Z-
dc.contributor.authorWang, Y-
dc.contributor.authorWang, R-
dc.contributor.authorKoohi-Moghadam, M-
dc.contributor.authorHu, L-
dc.contributor.authorXia, W-
dc.contributor.authorTang, H-
dc.contributor.authorWang, Y-
dc.contributor.authorLi, H-
dc.contributor.authorSun, H-
dc.date.accessioned2020-01-21T11:50:59Z-
dc.date.available2020-01-21T11:50:59Z-
dc.date.issued2019-
dc.identifier.citationPLoS Biology, 2019, v. 17 n. 6, article no. e3000292-
dc.identifier.issn1544-9173-
dc.identifier.urihttp://hdl.handle.net/10722/280268-
dc.description.abstractDespite 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.-
dc.languageeng-
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosbiology.org/plosonline/?request=index-html-
dc.relation.ispartofPLoS Biology-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectSilver-
dc.subjectGlucose metabolism-
dc.subjectMetabolites-
dc.subjectCitric acid cycle-
dc.subjectCell metabolism-
dc.titleDeciphering molecular mechanism of silver by integrated omic approaches enables enhancing its antimicrobial efficacy in E. coli-
dc.typeArticle-
dc.identifier.emailWang, H: wanghaib@hku.hk-
dc.identifier.emailYan, A: ayan8@hku.hk-
dc.identifier.emailXu, Z: zelingxu@connect.hku.hk-
dc.identifier.emailWang, R: u3002771@connect.hku.hk-
dc.identifier.emailLi, H: hylichem@hku.hk-
dc.identifier.emailSun, H: hsun@hku.hk-
dc.identifier.authorityYan, A=rp00823-
dc.identifier.authoritySun, H=rp00777-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pbio.3000292-
dc.identifier.pmid31181061-
dc.identifier.pmcidPMC6557469-
dc.identifier.scopuseid_2-s2.0-85067792949-
dc.identifier.hkuros308986-
dc.identifier.volume17-
dc.identifier.issue6-
dc.identifier.spagearticle no. e3000292-
dc.identifier.epagearticle no. e3000292-
dc.identifier.isiWOS:000473675900017-
dc.publisher.placeUnited States-

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