title: A novel fragment based strategy for membrane active antimicrobials against MRSA.
abstract: 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.
authors.affiliation: Singapore Eye Research Institute, 11 Third Hospital Avenue, #06-00, 168751, Singapore; Bioinformatics Institute (A*-STAR), 30 Biopolis Street, #07-01 Matrix, 138671, Singapore; Duke-NUS, SRP Neuroscience-Behavioural Disorders, Singapore.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Li
authors.affiliation: Singapore Eye Research Institute, 11 Third Hospital Avenue, #06-00, 168751, Singapore; Duke-NUS, SRP Neuroscience-Behavioural Disorders, Singapore.
authors.forename: Shouping
authors.initials: S
authors.lastname: Liu
authors.affiliation: Singapore Eye Research Institute, 11 Third Hospital Avenue, #06-00, 168751, Singapore; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, 119074, Singapore.
authors.forename: Jun-Jie
authors.initials: JJ
authors.lastname: Koh
authors.affiliation: Singapore Eye Research Institute, 11 Third Hospital Avenue, #06-00, 168751, Singapore.
authors.forename: Hanxun
authors.initials: H
authors.lastname: Zou
authors.affiliation: Singapore Eye Research Institute, 11 Third Hospital Avenue, #06-00, 168751, Singapore.
authors.forename: Rajamani
authors.initials: R
authors.lastname: Lakshminarayanan
authors.affiliation: Singapore Eye Research Institute, 11 Third Hospital Avenue, #06-00, 168751, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore.
authors.forename: Yang
authors.initials: Y
authors.lastname: Bai
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Pervushin
authors.affiliation: Singapore Eye Research Institute, 11 Third Hospital Avenue, #06-00, 168751, Singapore.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Singapore Eye Research Institute, 11 Third Hospital Avenue, #06-00, 168751, Singapore; Bioinformatics Institute (A*-STAR), 30 Biopolis Street, #07-01 Matrix, 138671, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543, Singapore. Electronic address: chandra@bii.a-star.edu.sg.
authors.forename: Chandra
authors.initials: C
authors.lastname: Verma
authors.affiliation: Singapore Eye Research Institute, 11 Third Hospital Avenue, #06-00, 168751, Singapore; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, 119074, Singapore; School of Chemical and Biomedical Engineering, Nanyang Technological University, 62 Nanyang Drive, 637459, Singapore; Duke-NUS, SRP Neuroscience-Behavioural Disorders, Singapore. Electronic address: rwbeuerman@gmail.com.
authors.forename: Roger W
authors.initials: RW
authors.lastname: Beuerman
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D003315:Cornea / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D056004:Molecular Dynamics Simulation; D011817:Rabbits; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000821:virology; D044004:Xanthones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000890:Anti-Infective Agents; D005452:Fluoresceins; D044004:Xanthones; C007740:fluorexon
keywords: Fragment based drug design; Membrane active antimicrobials; Molecular dynamics simulations; Pharmacophore model