Insights into idarubicin antimicrobial activity against methicillin-resistant Staphylococcus aureus

Background MRSA is a major concern in community settings and in health care. The emergence of biofilms and persister cells substantially increases its antimicrobial resistance. It is very urgent to develop new antimicrobials to solve this problem. Objective Idarubicin was profiled to assess its anti...

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Autores principales:	Pengfei She, Shijia Li, Linying Zhou, Zhen Luo, Jinfeng Liao, Lanlan Xu, Xianghai Zeng, Ti Chen, Yaqian Liu, Yong Wu
Formato:	article
Lenguaje:	EN
Publicado:	Taylor & Francis Group 2020
Materias:	drug repurposing idarubicin skin and soft tissue infections methicillin-resistant staphylococcus aureus topoisomerase ii cell membrane Infectious and parasitic diseases RC109-216
Acceso en línea:	https://doaj.org/article/0685297342d941f99f5fcefad9bd3710
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spelling	oai:doaj.org-article:0685297342d941f99f5fcefad9bd37102021-11-17T14:21:58ZInsights into idarubicin antimicrobial activity against methicillin-resistant Staphylococcus aureus2150-55942150-560810.1080/21505594.2020.1770493https://doaj.org/article/0685297342d941f99f5fcefad9bd37102020-12-01T00:00:00Zhttp://dx.doi.org/10.1080/21505594.2020.1770493https://doaj.org/toc/2150-5594https://doaj.org/toc/2150-5608Background MRSA is a major concern in community settings and in health care. The emergence of biofilms and persister cells substantially increases its antimicrobial resistance. It is very urgent to develop new antimicrobials to solve this problem. Objective Idarubicin was profiled to assess its antimicrobial effects in vitro and in vivo, and the underlying mechanisms. Methods We investigated the antimicrobial effects of idarubicin against MRSA by time-kill analysis. The antibiofilm efficacy of idarubicin was assessed by crystal violet and XTT staining, followed by laser confocal microscopy observation. The mechanisms underlying the antimicrobial effects were studied by transmission electron microscopy, all-atom molecular dynamic simulations, SYTOX staining, surface plasma resonance, and DNA gyrase inhibition assay. Further, we addressed the antimicrobial efficacy in wound and subcutaneous abscess infection in vivo. Results Idarubicin kills MRSA cells by disrupting the lipid bilayers and interrupting the DNA topoisomerase IIA subunits, and idarubicin shows synergistic antimicrobial effects with fosfomycin. Through synergy with a single dose treatment fosfomycin and the addition of the cell protector amifostine, the cytotoxicity and cardiotoxicity of idarubicin were significantly reduced without affecting its antimicrobial effects. Idarubicin alone or in combination with fosfomycin exhibited considerable efficacy in a subcutaneous abscess mouse model of MRSA infection. In addition, idarubicin also showed a low probability of causing resistance and good postantibiotic effects. Conclusions Idarubicin and its analogs have the potential to become a new class of antimicrobials for the treatment of MRSA-related infections.Pengfei SheShijia LiLinying ZhouZhen LuoJinfeng LiaoLanlan XuXianghai ZengTi ChenYaqian LiuYong WuTaylor & Francis Grouparticledrug repurposingidarubicinskin and soft tissue infectionsmethicillin-resistant staphylococcus aureustopoisomerase iicell membraneInfectious and parasitic diseasesRC109-216ENVirulence, Vol 11, Iss 1, Pp 636-651 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	drug repurposing idarubicin skin and soft tissue infections methicillin-resistant staphylococcus aureus topoisomerase ii cell membrane Infectious and parasitic diseases RC109-216
spellingShingle	drug repurposing idarubicin skin and soft tissue infections methicillin-resistant staphylococcus aureus topoisomerase ii cell membrane Infectious and parasitic diseases RC109-216 Pengfei She Shijia Li Linying Zhou Zhen Luo Jinfeng Liao Lanlan Xu Xianghai Zeng Ti Chen Yaqian Liu Yong Wu Insights into idarubicin antimicrobial activity against methicillin-resistant Staphylococcus aureus
description	Background MRSA is a major concern in community settings and in health care. The emergence of biofilms and persister cells substantially increases its antimicrobial resistance. It is very urgent to develop new antimicrobials to solve this problem. Objective Idarubicin was profiled to assess its antimicrobial effects in vitro and in vivo, and the underlying mechanisms. Methods We investigated the antimicrobial effects of idarubicin against MRSA by time-kill analysis. The antibiofilm efficacy of idarubicin was assessed by crystal violet and XTT staining, followed by laser confocal microscopy observation. The mechanisms underlying the antimicrobial effects were studied by transmission electron microscopy, all-atom molecular dynamic simulations, SYTOX staining, surface plasma resonance, and DNA gyrase inhibition assay. Further, we addressed the antimicrobial efficacy in wound and subcutaneous abscess infection in vivo. Results Idarubicin kills MRSA cells by disrupting the lipid bilayers and interrupting the DNA topoisomerase IIA subunits, and idarubicin shows synergistic antimicrobial effects with fosfomycin. Through synergy with a single dose treatment fosfomycin and the addition of the cell protector amifostine, the cytotoxicity and cardiotoxicity of idarubicin were significantly reduced without affecting its antimicrobial effects. Idarubicin alone or in combination with fosfomycin exhibited considerable efficacy in a subcutaneous abscess mouse model of MRSA infection. In addition, idarubicin also showed a low probability of causing resistance and good postantibiotic effects. Conclusions Idarubicin and its analogs have the potential to become a new class of antimicrobials for the treatment of MRSA-related infections.
format	article
author	Pengfei She Shijia Li Linying Zhou Zhen Luo Jinfeng Liao Lanlan Xu Xianghai Zeng Ti Chen Yaqian Liu Yong Wu
author_facet	Pengfei She Shijia Li Linying Zhou Zhen Luo Jinfeng Liao Lanlan Xu Xianghai Zeng Ti Chen Yaqian Liu Yong Wu
author_sort	Pengfei She
title	Insights into idarubicin antimicrobial activity against methicillin-resistant Staphylococcus aureus
title_short	Insights into idarubicin antimicrobial activity against methicillin-resistant Staphylococcus aureus
title_full	Insights into idarubicin antimicrobial activity against methicillin-resistant Staphylococcus aureus
title_fullStr	Insights into idarubicin antimicrobial activity against methicillin-resistant Staphylococcus aureus
title_full_unstemmed	Insights into idarubicin antimicrobial activity against methicillin-resistant Staphylococcus aureus
title_sort	insights into idarubicin antimicrobial activity against methicillin-resistant staphylococcus aureus
publisher	Taylor & Francis Group
publishDate	2020
url	https://doaj.org/article/0685297342d941f99f5fcefad9bd3710
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Insights into idarubicin antimicrobial activity against methicillin-resistant Staphylococcus aureus

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