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Felodipine enhances aminoglycosides efficacy against implant infections caused by methicillin-resistant Staphylococcus aureus, persisters and biofilms

Methicillin-resistant Staphylococcus aureus (MRSA), biofilms, and persisters are three major factors leading to recurrent and recalcitrant implant infections. Although antibiotics are still the primary treatment for chronic implant infections in clinical, only few drugs are effective in clearing per...

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Autores principales: Zhang, Shutao, Qu, Xinhua, Jiao, Juyang, Tang, Haozheng, Wang, Minqi, Wang, You, Yang, Hongtao, Yuan, Weien, Yue, Bing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: KeAi Publishing 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8897655/
https://www.ncbi.nlm.nih.gov/pubmed/35310349
http://dx.doi.org/10.1016/j.bioactmat.2021.11.019
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author Zhang, Shutao
Qu, Xinhua
Jiao, Juyang
Tang, Haozheng
Wang, Minqi
Wang, You
Yang, Hongtao
Yuan, Weien
Yue, Bing
author_facet Zhang, Shutao
Qu, Xinhua
Jiao, Juyang
Tang, Haozheng
Wang, Minqi
Wang, You
Yang, Hongtao
Yuan, Weien
Yue, Bing
author_sort Zhang, Shutao
collection PubMed
description Methicillin-resistant Staphylococcus aureus (MRSA), biofilms, and persisters are three major factors leading to recurrent and recalcitrant implant infections. Although antibiotics are still the primary treatment for chronic implant infections in clinical, only few drugs are effective in clearing persisters and formed biofilms. Here, felodipine, a dihydropyridine calcium channel blocker, was reported for the first time to have antibacterial effects against MRSA, biofilm, and persisters. Even after continuous exposure to sub-lethal concentrations of felodipine, bacteria are less likely to develop resistance. Besides, low doses of felodipine enhances the antibacterial activity of gentamicin by inhibiting the expression of protein associated with aminoglycoside resistance (aacA-aphD). Next, biofilm eradication test and persisters killing assay suggested felodipine has an excellent bactericidal effect against formed biofilms and persisters. Furthermore, the result of protein profiling, and quantitative metabonomics analysis indicated felodipine reduce MRSA virulence (agrABC), biofilm formation and TCA cycle. Then, molecular docking showed felodipine inhibit the growth of persisters by binding to the H pocket of ClpP protease, which could lead to substantial protein degradation. Furthermore, murine infection models suggested felodipine in combination with gentamicin alleviate bacterial burden and inflammatory response. In conclusion, low dose of felodipine might be a promising agent for biomaterial delivery to enhance aminoglycosides efficacy against implant infections caused by MRSA, biofilm, and persisters.
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spelling pubmed-88976552022-03-17 Felodipine enhances aminoglycosides efficacy against implant infections caused by methicillin-resistant Staphylococcus aureus, persisters and biofilms Zhang, Shutao Qu, Xinhua Jiao, Juyang Tang, Haozheng Wang, Minqi Wang, You Yang, Hongtao Yuan, Weien Yue, Bing Bioact Mater Article Methicillin-resistant Staphylococcus aureus (MRSA), biofilms, and persisters are three major factors leading to recurrent and recalcitrant implant infections. Although antibiotics are still the primary treatment for chronic implant infections in clinical, only few drugs are effective in clearing persisters and formed biofilms. Here, felodipine, a dihydropyridine calcium channel blocker, was reported for the first time to have antibacterial effects against MRSA, biofilm, and persisters. Even after continuous exposure to sub-lethal concentrations of felodipine, bacteria are less likely to develop resistance. Besides, low doses of felodipine enhances the antibacterial activity of gentamicin by inhibiting the expression of protein associated with aminoglycoside resistance (aacA-aphD). Next, biofilm eradication test and persisters killing assay suggested felodipine has an excellent bactericidal effect against formed biofilms and persisters. Furthermore, the result of protein profiling, and quantitative metabonomics analysis indicated felodipine reduce MRSA virulence (agrABC), biofilm formation and TCA cycle. Then, molecular docking showed felodipine inhibit the growth of persisters by binding to the H pocket of ClpP protease, which could lead to substantial protein degradation. Furthermore, murine infection models suggested felodipine in combination with gentamicin alleviate bacterial burden and inflammatory response. In conclusion, low dose of felodipine might be a promising agent for biomaterial delivery to enhance aminoglycosides efficacy against implant infections caused by MRSA, biofilm, and persisters. KeAi Publishing 2021-11-24 /pmc/articles/PMC8897655/ /pubmed/35310349 http://dx.doi.org/10.1016/j.bioactmat.2021.11.019 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Zhang, Shutao
Qu, Xinhua
Jiao, Juyang
Tang, Haozheng
Wang, Minqi
Wang, You
Yang, Hongtao
Yuan, Weien
Yue, Bing
Felodipine enhances aminoglycosides efficacy against implant infections caused by methicillin-resistant Staphylococcus aureus, persisters and biofilms
title Felodipine enhances aminoglycosides efficacy against implant infections caused by methicillin-resistant Staphylococcus aureus, persisters and biofilms
title_full Felodipine enhances aminoglycosides efficacy against implant infections caused by methicillin-resistant Staphylococcus aureus, persisters and biofilms
title_fullStr Felodipine enhances aminoglycosides efficacy against implant infections caused by methicillin-resistant Staphylococcus aureus, persisters and biofilms
title_full_unstemmed Felodipine enhances aminoglycosides efficacy against implant infections caused by methicillin-resistant Staphylococcus aureus, persisters and biofilms
title_short Felodipine enhances aminoglycosides efficacy against implant infections caused by methicillin-resistant Staphylococcus aureus, persisters and biofilms
title_sort felodipine enhances aminoglycosides efficacy against implant infections caused by methicillin-resistant staphylococcus aureus, persisters and biofilms
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8897655/
https://www.ncbi.nlm.nih.gov/pubmed/35310349
http://dx.doi.org/10.1016/j.bioactmat.2021.11.019
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