Jianguo Li, Shouping Liu, Jun-Jie Koh, Hanxun Zou, Rajamani Lakshminarayanan, Yang Bai, Konstantin Pervushin, Lei Zhou, Chandra Verma, Roger W. Beuerman, A novel fragment based strategy for membrane active antimicrobials against MRSA, Biochimica et Biophysica Acta (BBA) - Biomembranes, Volume 1848, Issue 4, 2015, Pages 1023-1031, ISSN 0005-2736, https://doi.org/10.1016/j.bbamem.2015.01.001.
Membrane active antimicrobials are a promising new generation of antibiotics that hold the potential to avert antibiotic resistance. However, poor understanding of the action mechanism and the lack of general design principles have impeded their development. Here we extend the concept of fragment based drug design and propose a pharmacophore model based on first principles for the design of membrane active antimicrobials against Gram positive pathogens. Elaborating on a natural xanthone-based hydrophobic scaffold, two derivatives of the pharmacophore model are proposed, and these demonstrate excellent antimicrobial activity. Rigorous molecular dynamics simulations combined with biophysical experiments suggest a three-step mechanism of action (absorption-translocation-disruption) which allows us to identify key factors for the practical optimization of each fragment of the pharmacophore. Moreover, the model matches the structures of several membrane active antimicrobials which are currently in clinical trials. Our model provides a novel and rational approach for the design of bactericidal molecules that target the bacterial membrane.
This work is supported by funding from ETPL/10-S10FSH-008, NMRC BNIG13nov015, CBRG14may012, TCR/002-SERI/2008/R618 and SHF/FG603S/2013, FG538P/2013, Singapore.
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