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

doi:10.1016/j.ejmech.2018.09.072

Norbornane-based cationic antimicrobial peptidomimetics targeting the bacterial membrane

Eur J Med Chem. 2018 Dec 5:160:9-22. doi: 10.1016/j.ejmech.2018.09.072. Epub 2018 Oct 3.

Authors

Affiliations

¹ Cancer Research Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, 5000, Australia. Electronic address: shane.hickey@unisa.edu.au.
² The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
³ Centre for Chemistry and Biotechnology, School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Victoria, 3216, Australia.
⁴ Cancer Research Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
⁵ Research School of Chemistry, The Australian National University, Acton, ACT, 2601, Australia.
⁶ Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
⁷ Institute for Organic Chemistry, University of Duisburg-Essen, 45117, Essen, Germany.
⁸ Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Science, Royal Parade, Parkville, Victoria, 3052, Australia.
⁹ Centre for Chemistry and Biotechnology, School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Victoria, 3216, Australia. Electronic address: fred.pfeffer@deakin.edu.au.

Abstract

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.

Keywords: Amphiphilic; Antibacterial; Antimicrobial; Fluorescence; Naphthalimide; Norbornane and microscopy.

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Antimicrobial Cationic Peptides / chemical synthesis
Antimicrobial Cationic Peptides / chemistry
Antimicrobial Cationic Peptides / pharmacology*
Cell Membrane / drug effects
Dose-Response Relationship, Drug
Methicillin-Resistant Staphylococcus aureus / cytology
Methicillin-Resistant Staphylococcus aureus / drug effects*
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Norbornanes / chemistry
Norbornanes / pharmacology*
Peptidomimetics / chemical synthesis
Peptidomimetics / chemistry
Peptidomimetics / pharmacology*
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Antimicrobial Cationic Peptides
Norbornanes
Peptidomimetics

Abstract

MeSH terms

Substances

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