Insights into idarubicin antimicrobial activity against methicillin-resistant
Animals
Anti-Bacterial Agents
/ pharmacology
Biofilms
/ drug effects
Drug Repositioning
Drug Synergism
Female
Fosfomycin
/ pharmacology
Idarubicin
/ analogs & derivatives
Methicillin-Resistant Staphylococcus aureus
/ drug effects
Mice
Mice, Inbred C57BL
Microbial Sensitivity Tests
Molecular Dynamics Simulation
Specific Pathogen-Free Organisms
Staphylococcal Skin Infections
/ drug therapy
Drug repurposing
cell membrane
idarubicin
methicillin-resistant Staphylococcus aureus
skin and soft tissue infections
topoisomerase II
Journal
Virulence
ISSN: 2150-5608
Titre abrégé: Virulence
Pays: United States
ID NLM: 101531386
Informations de publication
Date de publication:
01 01 2020
01 01 2020
Historique:
pubmed:
20
5
2020
medline:
13
7
2021
entrez:
20
5
2020
Statut:
ppublish
Résumé
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. Idarubicin was profiled to assess its antimicrobial effects 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 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. Idarubicin and its analogs have the potential to become a new class of antimicrobials for the treatment of MRSA-related infections.
Sections du résumé
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
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
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.
Identifiants
pubmed: 32423280
doi: 10.1080/21505594.2020.1770493
pmc: PMC7549941
doi:
Substances chimiques
Anti-Bacterial Agents
0
Fosfomycin
2N81MY12TE
Idarubicin
ZRP63D75JW
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
636-651Références
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