Poster Presentation 6th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2017

The preparation of tetrameric proline-rich antimicrobial peptides against nosocomial Gram-negative bacteria (#53)

Wenyi Li 1 , Neil O'Brien-Simpson 2 , Julien Tailhades 3 , Akhter Hossain 1 , Frances Separovic 4 , John D Wade 1
  1. Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
  2. Melbourne Dental School, University of Melbourne, Parkville, VIC, Australia
  3. Biochemistry & Molecular Biology, Monash University, Clayton, VIC, Australia
  4. School of Chemistry, University of Melbourne, Parkville, VIC, Australia

Due to their broad-spectrum activity and distinct modes of action, antimicrobial peptides are considered as potential alternatives to combat the widespread adapting resistance of pathogens to conventional antibiotics. Among them, the proline-rich antimicrobial peptides (PrAMPs) family has been extensively studied as potential agents for a new generation of antibiotics1.

Previously, we showed by high resolution microscopy and flow cytometry an alteration of mechanism of antibacterial action of a designed PrAMP, Chex1-Arg20, with increasing valency from monomer to dimer and tetramer2. As well, this shift in mechanism was supported by model membrane interaction study with the PrAMP multimers. Furthermore, the effects of a series of N- and C-terminal modifications of the monomeric PrAMP, Chex1-Arg20, were studied on a panel of Gram-negative bacteria3. Use of dedicated solid phase synthesis linkers allowed peptide C-terminal modifications with hydrazide or alcohol functions which were shown to significantly extended their antibacterial activity against A. baumannii and P. aeruginosa4.

These engineered PrAMPs, modified Chex1-Arg20 and tetrameric forms, highlight the value of solid phase synthesis to advance the development of novel compounds with strong activity against nosocomial Gram-negative bacteria (E. coli, K. pneumonia, A. baumannii and P. aeruginosa).

  1. W. Li, J. Tailhades, N. O’Brien-Simpson, F. Separovic, L. Otvos Jr, M.A. Hossain and J. Wade, Amino Acids, 2014, 46, 2287-2294.
  2. W. Li, N.M. O'Brien-Simpson, J. Tailhades, N. Pantarat, R.M. Dawson, L. Otvos, Jr., E.C. Reynolds, F. Separovic, M.A. Hossain and J.D. Wade, Chem. Biol., 2015, 22, 1250-1258.
  3. W. Li, J. Tailhades, M.A. Hossain, N.M. O’Brien-Simpson, E.C. Reynolds, L. Otvos, F. Separovic and J.D. Wade, Aust. J. Chem., 2015, 68, 1373-1378.
  4. W. Li, N.M. O’Brien-Simpson, S. Yao, E.C. Reynolds, R.M. Dawson, L. Otvos, M.A. Hossain, F. Separovic and J.D. Wade. Chem. Eur. J., 2017, 23, 390-396.