In Vitro and in Vivo Evaluation of Membrane-Active Flavone Amphiphiles: Semisynthetic Kaempferol-Derived Antimicrobials against Drug-Resistant Gram-Positive Bacteria

Because of the rapid increase in bacterial resistance, there is an urgent need for developing new antimicrobial agents to combat multidrug-resistant pathogens. In this study, we designed and synthesized a series of kaempferol derivatives as antimicrobial agents biomimicking the structural properties...

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Veröffentlicht in:Journal of medicinal chemistry 2020-06, Vol.63 (11), p.5797-5815
Hauptverfasser: Lin, Shuimu, Li, Hongxia, Tao, Yiwen, Liu, Jiayong, Yuan, Wenchang, Chen, Yongzhi, Liu, Ying, Liu, Shouping
Format: Artikel
Sprache:eng
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Zusammenfassung:Because of the rapid increase in bacterial resistance, there is an urgent need for developing new antimicrobial agents to combat multidrug-resistant pathogens. In this study, we designed and synthesized a series of kaempferol derivatives as antimicrobial agents biomimicking the structural properties and biological functions of host defense peptides. After fine-tuning of hydrophobic and cationic hydrophilic moieties linked to the flavone scaffold of kaempferol, we obtained a lead compound ( ) that displayed high membrane selectivity (>128), poor hemolytic activity, low cytotoxicity to mammalian cells, and excellent activity against Gram-positive bacteria (minimum inhibitory concentrations = 1.56 μg/mL), including methicillin-resistant . Compound can kill bacteria quickly by destroying the bacterial membranes and avoid developing bacterial resistance. Moreover, compound exhibited potent in vivo antibacterial activity against in a murine corneal infection model. These results indicated that compound had the therapeutic potential as a novel membrane-active antimicrobial to combat Gram-positive bacterial infections.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c00053