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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...

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Autores principales: Ma, Xinqian, Fu, Shining, Wang, Yifan, Zhao, Lili, Yu, Wenyi, He, Yukun, Ni, Wentao, Gao, Zhancheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
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.
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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
title_full Proteomics Study of the Synergistic Killing of Tigecycline in Combination With Aminoglycosides Against Carbapenem-Resistant Klebsiella pneumoniae
title_fullStr Proteomics Study of the Synergistic Killing of Tigecycline in Combination With Aminoglycosides Against Carbapenem-Resistant Klebsiella pneumoniae
title_full_unstemmed Proteomics Study of the Synergistic Killing of Tigecycline in Combination With Aminoglycosides Against Carbapenem-Resistant Klebsiella pneumoniae
title_short Proteomics Study of the Synergistic Killing of Tigecycline in Combination With Aminoglycosides Against Carbapenem-Resistant Klebsiella pneumoniae
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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