{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T13:45:05Z","timestamp":1776087905635,"version":"3.50.1"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T00:00:00Z","timestamp":1656547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014764","name":"China International Medical Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014764","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Co-administration of antibiotics with synergistic effects is one method to combat carbapenem-resistant organisms. Although the synergistic effects of tigecycline combined with aminoglycosides against carbapenem-resistant Klebsiella pneumoniae (CRKP) have been demonstrated <jats:italic>in vitro<\/jats:italic> and in animal models, the underlying mechanism remains elusive. Here we used proteomics analysis to assess the short-term bacterial responses to tigecycline and aminoglycosides alone or in combination. Emergence of tigecycline resistance during treatment and the susceptibility of tigecycline-resistant strains to aminoglycosides was further evaluated. The proteomic responses to tigecycline and aminoglycosides were divergent in monotherapy, with proteomic alterations to combination therapy dominated by tigecycline. Adaptive responses to tigecycline were associated with the upregulation of oxidative phosphorylation and translation-related proteins. These responses might confer CRKP hypersensitivity towards aminoglycosides by increasing the drug uptake and binding targets. Meanwhile, tigecycline might perturb adaptive responses to aminoglycosides through inhibition of heat shock response. Tigecycline-resistant strains could be isolated within 24\u00a0h exposure even in strains without heteroresistance, and the sensitivity to aminoglycosides significantly increased in resistant strains. Overall, these findings demonstrated that adaption to tigecycline in CRKP was a double-edged sword associated with the synergistic killing in tigecycline\u2013aminoglycoside combination. Evolutionary hypersensitivity can provide novel insight into the mechanisms of antibiotic synergistic effects.<\/jats:p>","DOI":"10.3389\/fcimb.2022.920761","type":"journal-article","created":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T09:37:54Z","timestamp":1656581874000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Proteomics Study of the Synergistic Killing of Tigecycline in Combination With Aminoglycosides Against Carbapenem-Resistant Klebsiella pneumoniae"],"prefix":"10.3389","volume":"12","author":[{"given":"Xinqian","family":"Ma","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shining","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yifan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lili","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenyi","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukun","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wentao","family":"Ni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhancheng","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2013315118","article-title":"Real-Time Measurements of Aminoglycoside Effects on Protein Synthesis in Live Cells","volume":"118","author":"Aguirre Rivera","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B2","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/185022a0","article-title":"Damage by Streptomycin to the Cell Membrane of Escherichia Coli","volume":"185","author":"Anand","year":"1960","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/185023a0","article-title":"Uptake of Streptomycin by Escherichia Coli","volume":"185","author":"Anand","year":"1960","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1038\/s41579-019-0218-1","article-title":"Mechanisms and Clinical Relevance of Bacterial Heteroresistance","volume":"17","author":"Andersson","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1627","DOI":"10.1038\/s41564-019-0480-z","article-title":"Antibiotic Combinations That Exploit Heteroresistance to Multiple Drugs Effectively Control Infection","volume":"4","author":"Band","year":"2019","journal-title":"Nat. Microbiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1038\/s41579-020-00443-1","article-title":"Proximate and Ultimate Causes of the Bactericidal Action of Antibiotics","volume":"19","author":"Baquero","year":"2021","journal-title":"Nat. Rev. Microbiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1038\/s41586-018-0278-9","article-title":"Species-Specific Activity of Antibacterial Drug Combinations","volume":"559","author":"Brochado","year":"2018","journal-title":"Nature"},{"key":"B8","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1111\/mmi.12884","article-title":"Escherichia Coli Persister Cells Suppress Translation by Selectively Disassembling and Degrading Their Ribosomes","volume":"95","author":"Cho","year":"2015","journal-title":"Mol. Microbiol."},{"key":"B9","article-title":"Performance Standards for Antimicrobial Susceptibility Testing","volume-title":"M100","year":"2020"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e01999","DOI":"10.1128\/AAC.01999-19","article-title":"Multidrug Adaptive Resistance of Pseudomonas Aeruginosa Swarming Cells","volume":"64","author":"Coleman Shannon","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"B11","first-page":"93","article-title":"Misreading of RNA Codewords Induced by Aminoglycoside Antibiotics","volume":"1","author":"Davies","year":"1965","journal-title":"Mol. Pharmacol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"6164","DOI":"10.1073\/pnas.83.16.6164","article-title":"Misread Protein Creates Membrane Channels: An Essential Step in the Bactericidal Action of Aminoglycosides","volume":"83","author":"Davis","year":"1986","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B13","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.mib.2021.09.006","article-title":"Leveraging Laboratory and Clinical Studies to Design Effective Antibiotic Combination Therapy","volume":"64","author":"Davis","year":"2021","journal-title":"Curr. Opin. Microbiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1093\/jac\/18.3.307","article-title":"Antagonistic Interactions of Macrolides and Synergimycins on Bacterial Ribosomes","volume":"18","author":"Di Giambattista","year":"1986","journal-title":"J. Antimicrob. Chemother."},{"key":"B15","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1016\/j.cmi.2019.04.013","article-title":"Management of Carbapenem-Resistant Enterobacteriaceae Infections","volume":"25","author":"Durante-Mangoni","year":"2019","journal-title":"Clin. Microbiol. Infect."},{"key":"B16","volume-title":"Breakpoint Tables for Interpretation of MICs and Zone Diameters (Version 8.1)","year":"2018"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1448","DOI":"10.1002\/jps.2600591017","article-title":"Kinetics and Mechanisms of Action of Drugs on Microorganisms. XI. Effect of Erythromycin and Its Supposed Antagonism With Lincomycin on the Microbial Growth of Escherichia Coli","volume":"59","author":"Garrett","year":"1970","journal-title":"J. Pharm. Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"10483","DOI":"10.1074\/jbc.M112.420380","article-title":"Chaperonins Fight Aminoglycoside-Induced Protein Misfolding and Promote Short-Term Tolerance in Escherichia Coli","volume":"288","author":"Goltermann","year":"2013","journal-title":"J. Biol. Chem."},{"key":"B19","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1126\/science.147.3659.746","article-title":"Drug Antagonism Between Lincomycin and Erythromycin","volume":"147","author":"Griffith","year":"1965","journal-title":"Science"},{"key":"B20","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/s1473-3099(16)30257-2","article-title":"Occurrence of Carbapenemase-Producing Klebsiella Pneumoniae and Escherichia Coli in the European Survey of Carbapenemase-Producing Enterobacteriaceae (EuSCAPE): A Prospective, Multinational Study","volume":"17","author":"Grundmann","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0119064","article-title":"Tigecycline Susceptibility and the Role of Efflux Pumps in Tigecycline Resistance in KPC-Producing Klebsiella Pneumoniae","volume":"10","author":"He","year":"2015","journal-title":"PloS One"},{"key":"B22","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1097\/qco.0000000000000012","article-title":"Aminoglycosides: How Should We Use Them in the 21st Century","volume":"26","author":"Jackson","year":"2013","journal-title":"Curr. Opin. Infect. Dis."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1080\/14787210.2017.1410434","article-title":"Combination Therapy for Extensively-Drug Resistant Gram-Negative Bacteria","volume":"15","author":"Karaiskos","year":"2017","journal-title":"Expert Rev. Anti Infect. Ther."},{"key":"B24","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1016\/j.molcel.2012.10.001","article-title":"Protein Aggregation Caused by Aminoglycoside Action Is Prevented by a Hydrogen Peroxide Scavenger","volume":"48","author":"Ling","year":"2012","journal-title":"Mol. Cell"},{"key":"B25","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1039\/c3mb70522f","article-title":"Fluctuation of Multiple Metabolic Pathways Is Required for Escherichia Coli in Response to Chlortetracycline Stress","volume":"10","author":"Lin","year":"2014","journal-title":"Mol. Biosyst."},{"key":"B26","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1146\/annurev-biochem-062917-011942","article-title":"Ribosome-Targeting Antibiotics: Modes of Action, Mechanisms of Resistance, and Implications for Drug Design","volume":"87","author":"Lin","year":"2018","journal-title":"Annu. Rev. Biochem."},{"key":"B27","doi-asserted-by":"publisher","first-page":"8173","DOI":"10.1073\/pnas.1509743112","article-title":"Antibiotic Efficacy is Linked to Bacterial Cellular Respiration","volume":"112","author":"Lobritz","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B28","doi-asserted-by":"publisher","first-page":"D1211","DOI":"10.1093\/nar\/gky869","article-title":"Iprox: An Integrated Proteome Resource","volume":"47","author":"Ma","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"671","DOI":"10.2217\/fmb-2019-0032","article-title":"Synergistic Effect of Doripenem in Combination With Cefoxitin and Tetracycline in Inhibiting NDM-1 Producing Bacteria","volume":"14","author":"Maryam","year":"2019","journal-title":"Future Microbiol."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2016.02007","article-title":"A Mechanism of Synergistic Effect of Streptomycin and Cefotaxime on CTX-M-15 Type \u03b2-Lactamase Producing Strain of E. Cloacae: A First Report","volume":"7","author":"Maryam","year":"2016","journal-title":"Front. Microbiol."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2017.00449","article-title":"Synergistic Effect of Doripenem and Cefotaxime to Inhibit CTX-M-15 Type \u03b2-Lactamases: Biophysical and Microbiological Views","volume":"8","author":"Maryam","year":"2017","journal-title":"Front. Pharmacol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"2097","DOI":"10.1093\/jac\/dkab122","article-title":"In Vitro and In Vivo Synergistic Effects of Tigecycline Combined With Aminoglycosides on Carbapenem-Resistant Klebsiella Pneumoniae","volume":"76","author":"Ni","year":"2021","journal-title":"J. Antimicrob. Chemother."},{"key":"B33","doi-asserted-by":"publisher","first-page":"4573","DOI":"10.1128\/aac.02463-14","article-title":"Antagonism Between Bacteriostatic and Bactericidal Antibiotics is Prevalent","volume":"58","author":"Ocampo","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"B34","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1016\/0005-2787(81)90177-5","article-title":"Competition Between Erythromycin and Virginiamycin for In Vitro Binding to the Large Ribosomal Subunit","volume":"654","author":"Parfait","year":"1981","journal-title":"Biochim. Biophys. Acta"},{"key":"B35","doi-asserted-by":"publisher","first-page":"S215","DOI":"10.1016\/s0924-8579(09)70005-6","article-title":"A Review of Tigecycline\u2013the First Glycylcycline","author":"Peterson","year":"2008","journal-title":"Int. J. Antimicrob. Agents"},{"key":"B36","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.ijantimicag.2016.04.017","article-title":"Current Perspectives on Tigecycline Resistance in Enterobacteriaceae: Susceptibility Testing Issues and Mechanisms of Resistance","volume":"48","author":"Pournaras","year":"2016","journal-title":"Int. J. Antimicrob. Agents"},{"key":"B37","doi-asserted-by":"publisher","first-page":"S206","DOI":"10.1093\/infdis\/jiz622","article-title":"The Colonization of Carbapenem-Resistant Klebsiella Pneumoniae: Epidemiology, Resistance Mechanisms, and Risk Factors in Patients Admitted to Intensive Care Units in China","volume":"221","author":"Qin","year":"2020","journal-title":"J. Infect. Dis."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1126\/science.1131542","article-title":"Structural Asymmetry of AcrB Trimer Suggests a Peristaltic Pump Mechanism","volume":"313","author":"Seeger","year":"2006","journal-title":"Science"},{"key":"B39","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.cmet.2019.06.009","article-title":"Bacterial Metabolism and Antibiotic Efficacy","volume":"30","author":"Stokes","year":"2019","journal-title":"Cell Metab."},{"key":"B40","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.mib.2020.05.012","article-title":"How Antibiotics Work Together: Molecular Mechanisms Behind Combination Therapy","volume":"57","author":"Sullivan","year":"2020","journal-title":"Curr. Opin. Microbiol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/s1473-3099(17)30753-3","article-title":"Discovery, Research, and Development of New Antibiotics: The WHO Priority List of Antibiotic-Resistant Bacteria and Tuberculosis","volume":"18","author":"Tacconelli","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"B42","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/s1473-3099(21)00399-6","article-title":"Clinical Outcomes and Bacterial Characteristics of Carbapenem-Resistant Klebsiella Pneumoniae Complex Among Patients From Different Global Regions (CRACKLE-2): A Prospective, Multicentre, Cohort Study","volume":"22","author":"Wang","year":"2022","journal-title":"Lancet Infect. Dis"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1830","DOI":"10.1038\/s41467-021-21942-6","article-title":"Translation Error Clusters Induced by Aminoglycoside Antibiotics","volume":"12","author":"Wohlgemuth","year":"2021","journal-title":"Nat. Commun."},{"key":"B44","doi-asserted-by":"publisher","first-page":"2126","DOI":"10.1074\/mcp.M115.050161","article-title":"Dynamic Proteome Response of Pseudomonas Aeruginosa to Tobramycin Antibiotic Treatment","volume":"14","author":"Wu","year":"2015","journal-title":"Mol. Cell Proteomics"},{"key":"B45","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.ebiom.2017.04.032","article-title":"Nationwide Surveillance of Clinical Carbapenem-Resistant Enterobacteriaceae (CRE) Strains in China","volume":"19","author":"Zhang","year":"2017","journal-title":"EBioMedicine"}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.920761\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T09:38:01Z","timestamp":1656581881000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.920761\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,30]]},"references-count":45,"alternative-id":["10.3389\/fcimb.2022.920761"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2022.920761","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,30]]},"article-number":"920761"}}