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    Hydrophobicity Determines the Bacterial Killing Rate of alpha-Helical Antimicrobial Peptides and Influences the Bacterial Resistance Development

    Year: 2022

    Journal: J. Med. Chem., Volume 65, NOV 10, page 14701–14720

    Authors: Zhang, Minghui; Ouyang, Jianhong; Fu, Lei; Xu, Cheng; Ge, Yuke; Sun, Shuqing; Li, Xiangyuan; Lai, Shian; Ke, Hengte; Yuan, Bing; Yang, Kai; Yu, Haining; Gao, Lianghui; Wang, Yipeng

    Organizations: National Natural Science Foundation of China [32070439, 21673021, 31872223]; Key Research & Development Plan in Social Development of Jiangsu Province [BE2022723]; Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD)

    Rapid antimicrobial action is an important advantage of antimicrobial peptides (AMPs) over antibiotics, which is also a reason for AMPs being less likely to induce bacterial resistance. However, the structural parameters and underlying mechanisms affecting the bacterial killing rate of AMPs remain unknown. In this study, we performed a structure-activity relationship (SAR) study using As-CATH4 and 5 as templates. We revealed that hydrophobicity, rather than other characteristics, is the critical structural parameter determining the bacterial killing rate of alpha-helical AMPs. With the hydrophobicity increase, the action rates of AMPs including bacterial binding, lipopolysaccharides neutralization, and outer and inner membrane permeabilization increased. Additionally, the higher hydrophobic AMPs with enhanced bacterial killing rates possess better in vivo therapeutic potency and a lower propensity to induce bacterial resistance. These findings revealed the importance of the bacterial killing rate for AMPs and are of great significance to the design and optimization of AMP-related drugs.
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