Abstract
Here we show that a new class of antibiotics-acyldepsipeptides-has antibacterial activity against Gram-positive bacteria in vitro and in several rodent models of bacterial infection. The acyldepsipeptides are active against isolates that are resistant to antibiotics in clinical application, implying a new target, which we identify as ClpP, the core unit of a major bacterial protease complex. ClpP is usually tightly regulated and strictly requires a member of the family of Clp-ATPases and often further accessory proteins for proteolytic activation. Binding of acyldepsipeptides to ClpP eliminates these safeguards. The acyldepsipeptide-activated ClpP core is capable of proteolytic degradation in the absence of the regulatory Clp-ATPases. Such uncontrolled proteolysis leads to inhibition of bacterial cell division and eventually cell death.
Publication types
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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 / classification*
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Anti-Bacterial Agents / pharmacokinetics
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Anti-Bacterial Agents / pharmacology*
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Anti-Bacterial Agents / toxicity
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Bacillus subtilis / drug effects
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Bacteria / drug effects*
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Bacteria / enzymology
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Bacteria / metabolism*
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Depsipeptides / metabolism
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Depsipeptides / pharmacokinetics
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Depsipeptides / pharmacology*
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Depsipeptides / toxicity
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Drug Resistance, Multiple, Bacterial
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Endopeptidase Clp / metabolism*
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Escherichia coli / drug effects
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Escherichia coli Proteins / metabolism*
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Female
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Mice
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Molecular Structure
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Mutation
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Pneumococcal Infections / drug therapy
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Pneumococcal Infections / microbiology
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Protein Binding
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Protein Processing, Post-Translational
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Rats
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Rats, Wistar
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Sepsis / drug therapy
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Sepsis / microbiology
Substances
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Anti-Bacterial Agents
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Depsipeptides
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Escherichia coli Proteins
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ClpP protease, E coli
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Endopeptidase Clp