pexiganan and Hemolysis

Host-defense peptides (HDPs) such as magainin 2 have emerged as potential therapeutic agents combating antibiotic resistance. Inspired by their structures and mechanism of action, herein we report the first example of antimicrobial helical sulfono-γ-AApeptide foldamers. The lead molecule displays broad-spectrum and potent antimicrobial activity against multi-drug-resistant Gram-positive and Gram-negative bacterial pathogens. Time-kill studies and fluorescence microscopy suggest that sulfono-γ-AApeptides eradicate bacteria by taking a mode of action analogous to that of HDPs. Clear structure-function relationships exist in the studied sequences. Longer sequences, presumably adopting more-defined helical structures, are more potent than shorter ones. Interestingly, the sequence with less helical propensity in solution could be more selective than the stronger helix-forming sequences. Moreover, this class of antimicrobial agents are resistant to proteolytic degradation. These results may lead to the development of a new class of antimicrobial foldamers combating emerging antibiotic-resistant pathogens.

Topics: Amino Acids, Sulfur; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Cell Proliferation; Cells, Cultured; Erythrocytes; Gram-Negative Bacteria; Hemolysis; Humans; Microbial Sensitivity Tests; Microscopy, Fluorescence; Models, Molecular; Molecular Structure; Peptide Fragments; Peptidomimetics; Scattering, Small Angle; Structure-Activity Relationship

The emergence of multidrug resistant bacteria compounded by the depleting arsenal of antibiotics has accelerated efforts toward development of antibiotics with novel mechanisms of action. In this report, we present a series of small molecular antibacterial peptoid mimics which exhibit high in vitro potency against a variety of Gram-positive and Gram-negative bacteria, including drug-resistant species such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. The highlight of these compounds is their superior activity against the major nosocomial pathogen Pseudomonas aeruginosa. Nontoxic toward mammalian cells, these rapidly bactericidal compounds primarily act by permeabilization and depolarization of bacterial membrane. Synthetically simple and selectively antibacterial, these compounds can be developed into a newer class of therapeutic agents against multidrug resistant bacterial species.

Topics: Anti-Bacterial Agents; Chromatography, High Pressure Liquid; Drug Resistance, Microbial; Enterococcus faecium; Hemolysis; Magnetic Resonance Spectroscopy; Mass Spectrometry; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Microscopy, Electron, Scanning; Microscopy, Fluorescence; Molecular Mimicry; Peptoids; Spectrophotometry, Ultraviolet

In this report, we describe the synthesis of a new series of small amphiphilic aromatic compounds that mimic the essential properties of cationic antimicrobial peptides using Suzuki-Miyaura coupling. The new design allowed the easy tuning of the conformational restriction, controlled by introduction of intramolecular hydrogen bonds, and the overall hydrophobicity by modifications to the central ring and the side chains. This approach allowed us to better understand the influence of these features on the antimicrobial activity and selectivity. We found that the overall hydrophobicity had a more significant impact on antimicrobial and hemolytic activity than the conformational stiffness. A novel compound was discovered which has MICs of 0.78 μg/mL against S. Aureus and 6.25 μg/mL against E. Coli, similar to the well-known antimicrobial peptide, MSI-78.

Topics: Amino Acid Sequence; Antimicrobial Cationic Peptides; Bacteria; Drug Design; Hemolysis; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Microbial Sensitivity Tests; Molecular Sequence Data; Peptidomimetics