Helical Antimicrobial Sulfono-γ-AApeptides

• Published in: Journal of medicinal chemistry Vol. 58; no. 11; pp. 4802 - 4811
• Main Authors: Li, Yaqiong, Wu, Haifan, Teng, Peng, Bai, Ge, Lin, Xiaoyang, Zuo, Xiaobing, Cao, Chuanhai, Cai, Jianfeng
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.06.2015; Amer Chemical Soc
• Subjects: Amino Acids, Sulfur - chemistry; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacology; Cell Proliferation - drug effects; Cells, Cultured; Chemistry, Medicinal; Erythrocytes - drug effects; Gram-Negative Bacteria - drug effects; Hemolysis - drug effects; Humans; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Microscopy, Fluorescence; Models, Molecular; Molecular Structure; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; Peptidomimetics - chemistry; Peptidomimetics - pharmacology; Pharmacology & Pharmacy; Scattering, Small Angle; Science & Technology; Structure-Activity Relationship; HOST-DEFENSE PEPTIDES; POLYMERS; ANTIBACTERIAL PEPTIDES; DESIGN; POTENT; SYNTHETIC MIMICS; ANTIFUNGAL ACTIVITY; FOLDAMERS; IDENTIFICATION
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00537

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.