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.
Shane M Hickey  1 ,  Trent D Ashton  2 ,  Gareth Boer  3 ,  Christie A Bader  4 ,  Michael Thomas  5 ,  Alysha G Elliott  6 ,  Carsten Schmuck  7 ,  Heidi Y Yu  8 ,  Jian Li  8 ,  Roger L Nation  8 ,  Matthew A Cooper  6 ,  Sally E Plush  4 ,  Douglas A Brooks  4 ,  Frederick M Pfeffer  9
Affiliations
  • 1. Cancer Research Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, 5000, Australia. Electronic address: [email protected].
  • 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: [email protected].
PMID: 30316060 DOI: 10.1016/j.ejmech.2018.09.072
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.