期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 58, 期 11, 页码 4802-4811出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b00537
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资金
- NSF CAREER [1351265]
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [1351265] Funding Source: National Science Foundation
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-gamma-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-gamma-AApeptides eradicate bacteria by taking a mode of action analogous to that of HDPs. Clear structurefunction 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.
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