Poster Presentation The 16th Australian Peptide Conference 2025

Understanding the mechanism of Proline-rich antimicrobial peptides (#134)

Yujie Zhu 1 , John Wade 2 , Wenyi Li 1
  1. Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
  2. The University of Melbourne, Melbourne, VIC, Australia

Antimicrobial peptides (AMPs) have emerged as promising antimicrobial drug candidates in recent years due to their broad-spectrum activity and low propensity for resistance development1. Despite their many advantages, AMPs often suffer from poor stability, unfavourable pharmacokinetic properties, and potential toxicity. To overcome these limitations and enhance their activity, various chemical modification strategies have been explored2-4.

Unlike many AMPs that disrupt bacterial membranes, proline-rich antimicrobial peptides (PrAMPs) primarily target intracellular processes, specifically inhibiting protein synthesis via ribosomal inhibition5-7.

Our current research focuses on the structural modification of PrAMPs, aiming to understand the detailed binding mechanism with the bacterial ribosome. In this project, we substituted certain amino acids with fluorinated derivatives to evaluate the impact on antibacterial activity and the mechanism of their intracellular target. Collectively, our research will provide new strategies and directions for the structural optimisation of antimicrobial peptides, potentially advancing their prospects for clinical application.

 

References

  1. N. Mookherjee, M. A. Anderson, H. P. Haagsman and D. J. Davidson, Nat. Rev. Drug Discov., 2020, 19, 311-332, 10.1038/s41573-019-0058-8.
  2. S. Shabani, S. Hadjigol, W. Li, Z. Si, D. Pranantyo, M. B. Chan-Park, . . . G. G. Qiao, Nature Reviews Bioengineering, 2024, 2, 343–361, 10.1038/s44222-023-00143-4.
  3. W. Li, F. Separovic, N. M. O'Brien-Simpson and J. D. Wade, Chem. Soc. Rev., 2021, 50, 4932-4973, 10.1039/D0CS01026J.
  4. P. Chen, T. Zhang, C. Li, P. Praveen, K. Parisi, C. Beh, . . . C. Shang, Acta Biomater., 2025, 192, 446-460, 10.1016/j.actbio.2024.12.002.
  5. 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, 10.1007/s00726-014-1820-1.
  6. A. Krizsan, D. Volke, S. Weinert, N. Strater, D. Knappe and R. Hoffmann, Angew. Chem. Int. Ed., 2014, 53, 12236-12239, 10.1002/anie.201407145.
  7. K. Mangano, D. Klepacki, I. Ohanmu, C. Baliga, W. Huang, A. Brakel, . . . A. S. Mankin, Nat. Chem. Biol., 2023, 19, 1082-1090, 10.1038/s41589-023-01300-x.