Abstract
New strategies are urgently needed to target MRSA, a major global health problem and the leading cause of mortality from antibiotic-resistant infections in many countries. Here, we report a general approach to this problem exemplified by the design and synthesis of a vancomycin-d-octaarginine conjugate (V-r8) and investigation of its efficacy in addressing antibiotic-insensitive bacterial populations. V-r8 eradicated MRSA biofilm and persister cells in vitro, outperforming vancomycin by orders of magnitude. It also eliminated 97% of biofilm-associated MRSA in a murine wound infection model and displayed no acute dermal toxicity. This new dual-function conjugate displays enhanced cellular accumulation and membrane perturbation as compared to vancomycin. Based on its rapid and potent activity against biofilm and persister cells, V-r8 is a promising agent against clinical MRSA infections.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / pharmacology
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Anti-Bacterial Agents / therapeutic use*
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Anti-Bacterial Agents / toxicity
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Biofilms / drug effects*
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Cell Line
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Cell-Penetrating Peptides / chemical synthesis
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Cell-Penetrating Peptides / pharmacology
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Cell-Penetrating Peptides / therapeutic use*
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Cell-Penetrating Peptides / toxicity
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Drug Design
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Humans
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Male
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Methicillin-Resistant Staphylococcus aureus / drug effects
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Methicillin-Resistant Staphylococcus aureus / physiology*
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Mice, Inbred C57BL
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Microbial Sensitivity Tests
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Oligopeptides / chemical synthesis
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Oligopeptides / pharmacology
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Oligopeptides / therapeutic use
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Oligopeptides / toxicity
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Vancomycin / analogs & derivatives*
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Vancomycin / pharmacology
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Vancomycin / therapeutic use*
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Vancomycin / toxicity
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Vancomycin-Resistant Enterococci / drug effects
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Vancomycin-Resistant Enterococci / physiology
Substances
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Anti-Bacterial Agents
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Cell-Penetrating Peptides
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Oligopeptides
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octaarginine
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Vancomycin