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Title: Design and synthesis of amphiphilic xanthone-based, membrane-targeting antimicrobials with improved membrane selectivity
Authors: Zou, H.
Koh, J.-J.
Li, J.
Qiu, S.
Aung, T.T.
Lin, H.
Lakshminarayanan, R. 
Dai, X.
Tang, C.
Lim, F.H.
Zhou, L.
Tan, A.L.
Verma, C. 
Tan, D.T.H.
Chan, H.S.O. 
Saraswathi, P.
Cao, D.
Liu, S. 
Beuerman, R.W.
Issue Date: 28-Mar-2013
Citation: Zou, H., Koh, J.-J., Li, J., Qiu, S., Aung, T.T., Lin, H., Lakshminarayanan, R., Dai, X., Tang, C., Lim, F.H., Zhou, L., Tan, A.L., Verma, C., Tan, D.T.H., Chan, H.S.O., Saraswathi, P., Cao, D., Liu, S., Beuerman, R.W. (2013-03-28). Design and synthesis of amphiphilic xanthone-based, membrane-targeting antimicrobials with improved membrane selectivity. Journal of Medicinal Chemistry 56 (6) : 2359-2373. ScholarBank@NUS Repository.
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. © 2013 American Chemical Society.
Source Title: Journal of Medicinal Chemistry
ISSN: 00222623
DOI: 10.1021/jm301683j
Appears in Collections:Staff Publications

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