Molecular Design of Novel Membrane Targeting Antimicrobials with Improved Membrane Selectivity Using Natural Compound as a Scaffold

Abstract

Purpose: To set up a new platform for design and prediction of membrane targeting small organic molecules based antimicrobials with improved membrane selectivity

Methods: This work describes how to tune the amphiphilic conformation of α-mangostin, a natural compound with a hydrophobic xanthone scaffold, to improve the antimicrobial activity and selectivity toward Gram positive bacteria. A series of xanthone derivatives were obtained by cationic modification of free hydroxyl groups of α-mangostin at C3 and C6 positions with amines groups of different pKa values.

Results: The results show that the antimicrobial activities of the cationic xanthone derivatives can be generally predicted based on the pKa values of the corresponding amines. We have identified AM-0016 (3b) as the most potent compound in the series with potent antimicrobial activity with MIC values of 0.095-0.39 (µg/mL) against Gram-positive bacteria including MRSA, improved selectivity up to 200, rapid time-kill in 10-30mins, avoidance of antibiotic resistance and good biocompatibity. Biophysical studies and molecular dynamic simulations also revealed that 3b disrupted the bacterial membrane by forming an amphiphilic conformation with the cationic groups located at the hydrophobic-water interface. In contrast, conjugation moieties with low pKa value to the xanthone scaffold diminished the antimicrobial activities.

Conclusions: A series of novel antimicrobials have been designed and prepared by cationic modifications of α-mangostin, a natural xanthone with a planar hydrophobic core, to yield an amphiphilic structure which improves selectivity for bacterial membranes through the hydrophobic-water interface perturbation. This design strategy is important as we provide a new approach to modify natural compounds to yield excellent antimicrobial properties, high selectivity and safety. This strategy could improve “hits” in the development of new antibiotics for drug-resistant pathogens.

Keywords: 422 antibiotics/antifungals/antiparasitics