title: Design and synthesis of amphiphilic xanthone-based, membrane-targeting antimicrobials with improved membrane selectivity.
abstract: This work describes how to tune the amphiphilic conformation of α-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 α-mangostin with amine groups of different pKa values. Modified structures using moieties with high pKa 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-water interface. In contrast, moieties with low pKa values reduced the antimicrobial activity of the parent compound when conjugated to the xanthone scaffold. This strategy provides a new way to improve "hits" for the development of membrane-active antibiotics that target drug-resistant pathogens.
authors: Singapore Eye Research Institute, 11 Third Hospital Avenue, Singapore 168751, Singapore.
authors: Hanxun
authors: H
authors: Zou
authors: Jun-Jie
authors: JJ
authors: Koh
authors: Jianguo
authors: J
authors: Li
authors: Shengxiang
authors: S
authors: Qiu
authors: Thet Tun
authors: TT
authors: Aung
authors: Huifen
authors: H
authors: Lin
authors: Rajamani
authors: R
authors: Lakshminarayanan
authors: Xiaoping
authors: X
authors: Dai
authors: Charles
authors: C
authors: Tang
authors: Fang Hui
authors: FH
authors: Lim
authors: Lei
authors: L
authors: Zhou
authors: Ai Ling
authors: AL
authors: Tan
authors: Chandra
authors: C
authors: Verma
authors: Donald T H
authors: DT
authors: Tan
authors: Hardy Sze On
authors: HS
authors: Chan
authors: Padmanabhan
authors: P
authors: Saraswathi
authors: Derong
authors: D
authors: Cao
authors: Shouping
authors: S
authors: Liu
authors: Roger W
authors: RW
authors: Beuerman
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D001419:Bacteria / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D057927:Hydrophobic and Hydrophilic Interactions; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011817:Rabbits; D013379:Substrate Specificity; D044004:Xanthones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000900:Anti-Bacterial Agents; D044004:Xanthones