protegrin-1 and Sepsis

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.

Topics: 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 aeruginosa; Pseudomonas Infections; Sepsis

Topics: Analysis of Variance; Animals; Anti-Infective Agents; Antimicrobial Cationic Peptides; Colony Count, Microbial; Cytokines; Mice; Mice, Inbred BALB C; Proteins; Sepsis; Survival Analysis