A. Pellegrini et R. Von Fellenberg, Design of synthetic bactericidal peptides derived from the bactericidal domain P18-39 of aprotinin, BBA-PROT ST, 1433(1-2), 1999, pp. 122-131
Citations number
34
Categorie Soggetti
Biochemistry & Biophysics
Journal title
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEIN STRUCTURE AND MOLECULAR ENZYMOLOGY
A bactericidal domain, P18-39, of the proteinase inhibitor aprotinin, posse
sses the structural feature of two antiparallel beta-sheets connected by a
short turn. In order to understand the structural requirements for antibact
erial activity, two peptides, each having the sequence corresponding to a s
ingle beta-sheet structure of P18-39, were synthesized and their antibacter
ial properties investigated. One peptide, P18-28, with the sequence IIRYFYN
AKAG, was active against almost all the bacterial strains investigated. How
ever, the bactericidal activity of P18-28 was reduced compared to the paren
t molecule, P18-39. The other peptide, P29-39, with the sequence LCQTFVYGGC
R, was only weakly bactericidal against Pseudomonas aeruginosa. A peptide,
P18-26, devoid of the C-terminus dipeptide Ala-Gly of P18-28. retained the
bactericidal activity of P18-28 against most of the bacterial strains inves
tigated. Only Klebsiella pneumoniae, P. aeruginosa and Staphylococcus aureu
s were resistant to P18-26. Replacement of lysine 26 by arginine in P18-26
(IIRYFYNAR) improved the bactericidal activity. The retropeptide, RANYFYRII
, retained the antibacterial activity of IIRYFYNAR toward Gram-negative bac
teria, but it was less active against Gram-positive bacteria. The random pe
ptide, IANRIYRYF, was as bactericidal as IIRYFYNAR. Moreover, the random pe
ptide possessed, in contrast to IIRYFYNAR, a strong antifungal activity aga
inst Candida albicans. Elimination of the N-hydrophobic terminal Ile-Ile fr
om P18-26 (RYFYNAK) strongly reduced the bactericidal potency of the peptid
e, Attaching the hydrophobic peptide, FFVAP, to the C-terminal of P18-26 (I
IRYFYNAKFFVAP) increased the bactericidal potency of the peptides considera
bly. We concluded that the order of the amino acids in the sequence of the
peptides is not, per se, a critical feature for bactericidal activity. Hydr
ophobic interaction between peptide and bacterial membrane is probably the
most important feature involved in the bactericidal mechanism of the antibi
otic peptides. (C) 1999 Elsevier Science B.V. All rights reserved.