Abstract
The ClpXP protease is a critical bacterial intracellular protease that regulates protein turnover in many bacterial species. Here we identified a pharmacological inhibitor of the ClpXP protease, F2, and evaluated its action in Bacillus anthracis and Staphylococcus aureus. We found that F2 exhibited synergistic antimicrobial activity with cathelicidin antimicrobial peptides and antibiotics that target the cell well and/or cell membrane, such as penicillin and daptomycin, in B. anthracis and drug-resistant strains of S. aureus. ClpXP inhibition represents a novel therapeutic strategy to simultaneously sensitize pathogenic bacteria to host defenses and pharmaceutical antibiotics.
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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Amino Acid Sequence
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Anti-Bacterial Agents / pharmacology*
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Antimicrobial Cationic Peptides / pharmacology*
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Bacillus anthracis / drug effects
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Bacillus anthracis / genetics
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Bacteria / drug effects*
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Cathelicidins
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Cell Membrane / metabolism
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Drug Resistance, Bacterial
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Drug Synergism
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Endopeptidase Clp / antagonists & inhibitors*
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Escherichia coli Proteins / antagonists & inhibitors*
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Methicillin-Resistant Staphylococcus aureus / drug effects
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Molecular Sequence Data
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Protease Inhibitors / pharmacology*
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Staphylococcus aureus / drug effects
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Staphylococcus aureus / growth & development
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Tetrazoles / pharmacology
Substances
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Anti-Bacterial Agents
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Antimicrobial Cationic Peptides
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Escherichia coli Proteins
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F2 protease inhibitor
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Protease Inhibitors
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Tetrazoles
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ClpXP protease, E coli
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Endopeptidase Clp
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Cathelicidins