Abstract
Antibiotics with new mechanisms of action are urgently required to combat the growing health threat posed by resistant pathogenic microorganisms. We synthesized a family of peptidomimetic antibiotics based on the antimicrobial peptide protegrin I. Several rounds of optimization gave a lead compound that was active in the nanomolar range against Gram-negative Pseudomonas spp., but was largely inactive against other Gram-negative and Gram-positive bacteria. Biochemical and genetic studies showed that the peptidomimetics had a non-membrane-lytic mechanism of action and identified a homolog of the beta-barrel protein LptD (Imp/OstA), which functions in outer-membrane biogenesis, as a cellular target. The peptidomimetic showed potent antimicrobial activity in a mouse septicemia infection model. Drug-resistant strains of Pseudomonas are a serious health problem, so this family of antibiotics may have important therapeutic applications.
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 / chemical synthesis
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Anti-Bacterial Agents / metabolism
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Anti-Bacterial Agents / pharmacology*
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Antimicrobial Cationic Peptides / chemistry
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Bacterial Outer Membrane Proteins / chemistry
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Bacterial Outer Membrane Proteins / genetics
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Bacterial Outer Membrane Proteins / metabolism*
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Cell Membrane / metabolism*
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Drug Design
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Drug Resistance, Bacterial / genetics
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Genes, Bacterial
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Lipopolysaccharides / metabolism
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Mice
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Microbial Sensitivity Tests
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Molecular Mimicry
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Mutation
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Peptide Library
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Peptides / chemical synthesis
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Peptides / chemistry
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Peptides / metabolism
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Peptides / pharmacology*
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Protein Structure, Tertiary
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Pseudomonas Infections / drug therapy
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Pseudomonas Infections / microbiology
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Pseudomonas aeruginosa / drug effects*
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Pseudomonas aeruginosa / growth & development
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Pseudomonas aeruginosa / metabolism*
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Pseudomonas aeruginosa / ultrastructure
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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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Antimicrobial Cationic Peptides
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Bacterial Outer Membrane Proteins
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Lipopolysaccharides
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Peptide Library
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Peptides
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protegrin-1