Norbornane-based cationic antimicrobial peptidomimetics targeting the bacterial membrane
Shane M Hickey, Trent D Ashton, Gareth Boer, Christie A Bader, Michael Thomas, Alysha G Elliott, Carsten Schmuck, Heidi Y Yu, Jian Li, Roger L Nation, Matthew A Cooper, Sally E Plush, Douglas A Brooks, Frederick M Pfeffer
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER | Published : 2018
The design, synthesis and evaluation of a small series of potent amphiphilic norbornane antibacterial agents has been performed (compound 10 MIC = 0.25 μg/mL against MRSA). Molecular modelling indicates rapid aggregation of this class of antibacterial agent prior to membrane association and insertion. Two fluorescent analogues (compound 29 with 4-amino-naphthalimide and 34 with 4-nitrobenz-2-oxa-1,3-diazole fluorophores) with good activity (MIC = 0.5 μg/mL against MRSA) were also constructed and confocal microscopy studies indicate that the primary site of interaction for this family of compounds is the bacterial membrane.
Awarded by ARC
Awarded by Australian Research Council through LIEF
Awarded by National Institute of Allergy and Infectious Diseases of the National Institutes of Health
Awarded by NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
F.M.P., S.M.H., & T.D.A. thank the ARC (DP140100227) and the Strategic Research Centre for Chemistry and Biotechnology (Deakin University) for financial support and a top -up scholarship for S.M.H. The authors would also like to thank the Australian Research Council for funding Deakin University's Magnetic Resonance Facility through LIEF grant LE110100141. C.A.B was funded by a Future Industry Accelerator Research and Development Voucher Scheme. & R.L.N. are supported by a research grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (R01 A1098771). J.L. is an Australian NHMRC Senior Research Fellow, while M.A.C. is an Australian NHMRC Principal Research Fellow. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. The MIC and cytotoxicity assays were performed in collaboration with CO-ADD (Community for Open Antimicrobial Drug Discovery, co-add.org)  funded by the Wellcome Trust and The University of Queensland.