Structural determinants of antimicrobial and antiplasmodial activity and selectivity in histidine-rich amphipathic cationic peptides

A. James Mason, Wardi Moussaoui, Tamer Abdelrahman, Alyae Boukhari, Philippe Bertani, Arnaud Marquette, Peiman Shooshtarizaheh, Gilles Moulay, Nelly Boehm, Bernard Guerold, Ruairidh J.H. Sawers, Antoine Kichler, Marie Hélène Metz-Boutigue, Ermanno Candolfi, Gilles Prévost, Burkhard Bechinger

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


Designed histidine-rich amphipathic cationic peptides, such as LAH4, have enhanced membrane disruption and antibiotic properties when the peptide adopts an alignment parallel to the membrane surface. Although this was previously achieved by lowering the pH, here we have designed a new generation of histi-dine-rich peptides that adopt a surface alignment at neutral pH. In vitro, this new generation of peptides are powerful antibiotics in terms of the concentrations required for antibiotic activity; the spectrum of target bacteria, fungi, and parasites; and the speed with which they kill. Further modifications to the peptides, including the addition of more hydrophobic residues at the N terminus, the inclusion of a helix-breaking proline residue or using D-amino acids as building blocks, modulated the biophysical properties of the peptides and led to substantial changes in toxicity to human and parasite cells but had only a minimal effect on the antibacterial and antifungal activity. Using a range of biophysical methods, in particular solid-state NMR, we show that the peptides are highly efficient at disrupting the anionic lipid component of model membranes. However, we also show that effective pore formation in such model membranes may be related to, but is not essential for, high antimicrobial activity by cationic amphipathic helical pep-tides. The information in this study comprises a new layer of detail in the understanding of the action of cationic helical antimicrobial peptides and shows that rational design is capable of producing potentially therapeutic membrane active peptides with properties tailored to their function.

Original languageEnglish (US)
Pages (from-to)119-133
Number of pages15
JournalJournal of Biological Chemistry
Issue number1
StatePublished - Jan 2 2009

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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