Oral Presentation 8th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2022

Synthesis of CLipPA analogues of the antimicrobial peptide, paenipeptin C΄ (#4)

Juliana T. W. Tong 1 2 , Iman Kavianinia 2 3 , Paul W. R. Harris 1 2 3 , Margaret A. Brimble 1 2 3
  1. School of Chemical Sciences, The University of Auckland, Auckland, New Zealand
  2. Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
  3. School of Biological Sciences, The University of Auckland, Auckland, New Zealand

The continuing emergence and rapid dissemination of antimicrobial-resistant pathogens is recognised by the World Health Organisation as one of the greatest threats to humankind. It threatens our ability to treat common infections and the success of medical procedures (e.g. surgery and cancer chemotherapy). Importantly, infections caused by Gram-negative bacteria such as Escherichia coli are significantly more challenging to treat. Although the polymyxins are considered clinically successful lipopeptide antibiotics, and in fact represent the last line of defence against multi-drug resistant Gram-negative bacterial infections, they are associated with serious nephrotoxicity. Therefore, there is an urgent need to develop novel antimicrobial agents with improved efficacy and safety profiles to aid the fight against antimicrobial resistance. Paenipeptin C´ is a novel linear lipopeptide antibiotic based on a natural mixture of linear and cyclic lipopeptides from Paenibacillus sp. strain OSY-N. It demonstrated potent activity against both Gram-positive and Gram-negative bacteria, and more importantly, high antibacterial activity was achieved with low haemolytic activity. The amino acid sequence of paenipeptin C´, consisting of nine readily available amino acid residues and an N-terminal octanoyl moiety, allows for facile chemical modifications to finetune its therapeutic properties. Herein, analogues of paenipeptin C´ were synthesised by Fmoc-based solid phase peptide synthesis, and lipidation achieved using patented thiol‑ene technology, termed Cysteine Lipidation on a Peptide or Amino acid (CLipPA). This approach enabled site-specific S-lipidation with varying lipid moieties as their requisite vinyl esters in a single-step, under mild conditions. Antimicrobial evaluation towards both Gram-positive and Gram-negative bacterial strains indicated potent broad spectrum antimicrobial activity correlated with increasing hydrophobicity. Importantly, three analogues displayed minimum inhibitory concentration and minimum bactericidal concentration values in the low ug/mL range, comparable to other clinically used antibiotics, making them promising candidates for further development including cytotoxicity and nephrotoxicity testing.

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