Design and Synthesis of Amphiphilic Xanthone-Based, Membrane-Targeting Antimicrobials with Improved Membrane Selectivity

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• 作者：Hanxun Zou ; Jun-Jie Koh ; Jianguo Li ; Shengxiang Qiu ; Thet Tun Aung ; Huifen Lin ; Rajamani Lakshminarayanan ; Xiaoping Dai ; Charles Tang ; Fang Hui Lim ; Lei Zhou ; Ai Ling Tan ; Chandra Verma ; Donald T. H. Tan ; Hardy Sze On Chan ; Padmanabhan Saraswathi ; Derong Cao ; Shouping Liu ; Roger W. Beuerman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 28, 2013
• 年：2013
• 卷：56
• 期：6
• 页码：2359-2373
• 全文大小：706K
• 年卷期：v.56,no.6(March 28, 2013)
• ISSN：1520-4804

文摘

This work describes how to tune the amphiphilic conformation of 伪-mangostin, a natural compound that contains a hydrophobic xanthone scaffold, to improve its antimicrobial activity and selectivity for Gram-positive bacteria. A series of xanthone derivatives was obtained by cationic modification of the free C3 and C6 hydroxyl groups of 伪-mangostin with amine groups of different pK_a values. Modified structures using moieties with high pK_a values, such as AM-0016 (3b), exhibited potent antimicrobial properties against Gram-positive bacteria. Compound 3b also killed bacteria rapidly without inducing drug resistance and was nontoxic when applied topically. Biophysical studies and molecular dynamics simulations revealed that 3b targets the bacterial inner membrane, forming an amphiphilic conformation at the hydrophobic鈥搘ater interface. In contrast, moieties with low pK_a values reduced the antimicrobial activity of the parent compound when conjugated to the xanthone scaffold. This strategy provides a new way to improve 鈥渉its鈥?for the development of membrane-active antibiotics that target drug-resistant pathogens.