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.

Membrane‐Active Small Molecules: Designs Inspired by Antimicrobial Peptides

“…Combination strategies have already been considered in the field of macromolecular membrane-active agents. [53] Combination of other antibacterial agents with small-molecule mimics would solve many problems, not only in the case of www.chemmedchem.org chronic infections, but also for normali nfections caused by resistant bacteria. Future studies in the field can be directed toward this concept.…”

“…These compoundsd isplayed selective antibacterial activity against av ariety of Grampositive pathogens, including clinicali solates. [53] In further advancement of this work, cationic amino acids were coupled to the xanthone core to provide more potent and selective compounds (M r slightly greater than 1000 Da). [54] In arepresentative structure (Table8,S tructure 23), the four positive charges were contributed by the guanidineg roups of arginine.…”

“…[53] Subsequently,t he authors also studied the ability of xanthone derivatives to cure bacterial infection in the cornea of mice. [54] This study is another eye-opener to the immense possibilities these classes of compounds hold as next-generation antibiotics.…”

Efektivitas in vitro Alfa Mangostin Pada Pertumbuhan Bakteri Uropatogen Escherichia coli Multiresisten

“…Other Xanthones such as gamma mangostin and xanthon derivatives has bee show to have no antibacterial activity (Jindarat, 2014). The minimum inhibitory levels were obtained by the study conducted by Zou et al (2013) which showig that the α-mangostin less effective in killing gram-negative bacteria with the minimum inhibitory concentration >200 µg/mL. Uropathogenic Escherichia coli belongs to the gram-negative bacteria with outer cell membrane composed of lipopolysaccharide.…”

“…A study conducted by Seesom et al (2013) stated that α-mangostin has the potential to inhibit the growth of Mycobacterium tuberculosis. Other studies on antibacterial activity of mangostin was coducted by Zou et al (2013) stating that the test on the effect of mangostin against Pseudomonas aeruginosa and Klebsiella pneumoniae resulted in MIC of 40-50 µg/mL. The studies on effect of α-mangostin against several bacteria including Escherichia coli have also been carried out by Al Massarani et al in 2013 resulting in E. coli IC 50 >200 µg/mL.…”