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Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa.

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  • 2010-02-20
Published in:
  • Science (New York, N.Y.). - 2010
Animals
Anti-Bacterial Agents
Antimicrobial Cationic Peptides
Bacterial Outer Membrane Proteins
Cell Membrane
Drug Design
Drug Resistance, Bacterial
Genes, Bacterial
Lipopolysaccharides
Mice
Microbial Sensitivity Tests
Molecular Mimicry
Mutation
Peptide Library
Peptides
Protein Structure, Tertiary
Pseudomonas Infections
Pseudomonas aeruginosa
Sepsis
English 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.
Language
  • English
Open access status
green
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Persistent URL
https://sonar.ch/global/documents/75335
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