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Proteomics Study of the Synergistic Killing of Tigecycline in Combination With Aminoglycosides Against Carbapenem-Resistant Klebsiella pneumoniae
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 in vitro and in animal mode...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9280366/ https://www.ncbi.nlm.nih.gov/pubmed/35846751 http://dx.doi.org/10.3389/fcimb.2022.920761 |
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author | Ma, Xinqian Fu, Shining Wang, Yifan Zhao, Lili Yu, Wenyi He, Yukun Ni, Wentao Gao, Zhancheng |
author_facet | Ma, Xinqian Fu, Shining Wang, Yifan Zhao, Lili Yu, Wenyi He, Yukun Ni, Wentao Gao, Zhancheng |
author_sort | Ma, Xinqian |
collection | PubMed |
description | 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 in vitro 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 h 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–aminoglycoside combination. Evolutionary hypersensitivity can provide novel insight into the mechanisms of antibiotic synergistic effects. |
format | Online Article Text |
id | pubmed-9280366 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92803662022-07-15 Proteomics Study of the Synergistic Killing of Tigecycline in Combination With Aminoglycosides Against Carbapenem-Resistant Klebsiella pneumoniae Ma, Xinqian Fu, Shining Wang, Yifan Zhao, Lili Yu, Wenyi He, Yukun Ni, Wentao Gao, Zhancheng Front Cell Infect Microbiol Cellular and Infection Microbiology 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 in vitro 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 h 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–aminoglycoside combination. Evolutionary hypersensitivity can provide novel insight into the mechanisms of antibiotic synergistic effects. Frontiers Media S.A. 2022-06-30 /pmc/articles/PMC9280366/ /pubmed/35846751 http://dx.doi.org/10.3389/fcimb.2022.920761 Text en Copyright © 2022 Ma, Fu, Wang, Zhao, Yu, He, Ni and Gao https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cellular and Infection Microbiology Ma, Xinqian Fu, Shining Wang, Yifan Zhao, Lili Yu, Wenyi He, Yukun Ni, Wentao Gao, Zhancheng Proteomics Study of the Synergistic Killing of Tigecycline in Combination With Aminoglycosides Against Carbapenem-Resistant Klebsiella pneumoniae |
title | Proteomics Study of the Synergistic Killing of Tigecycline in Combination With Aminoglycosides Against Carbapenem-Resistant Klebsiella pneumoniae
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title_full | Proteomics Study of the Synergistic Killing of Tigecycline in Combination With Aminoglycosides Against Carbapenem-Resistant Klebsiella pneumoniae
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title_fullStr | Proteomics Study of the Synergistic Killing of Tigecycline in Combination With Aminoglycosides Against Carbapenem-Resistant Klebsiella pneumoniae
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title_full_unstemmed | Proteomics Study of the Synergistic Killing of Tigecycline in Combination With Aminoglycosides Against Carbapenem-Resistant Klebsiella pneumoniae
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title_short | Proteomics Study of the Synergistic Killing of Tigecycline in Combination With Aminoglycosides Against Carbapenem-Resistant Klebsiella pneumoniae
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title_sort | proteomics study of the synergistic killing of tigecycline in combination with aminoglycosides against carbapenem-resistant klebsiella pneumoniae |
topic | Cellular and Infection Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9280366/ https://www.ncbi.nlm.nih.gov/pubmed/35846751 http://dx.doi.org/10.3389/fcimb.2022.920761 |
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