Antimicrobial activity of novel dendrimeric peptides obtained by phage display selection and rational modification.
A large 10-mer phage peptide library was panned against whole Escherichia coli cells, and an antimicrobial peptide (QEKIRVRLSA) was selected. The peptide was synthesized in monomeric and dendrimeric tetrabranched form (multiple antigen peptide [MAP]), which generally allows a dramatic increase of peptide stability to peptidases and proteases. The antibacterial activity of the dendrimeric peptide against E. coli was much higher than that of the monomeric form. Modification of the original sequence, by residue substitution or sequence shortening, produced three different MAPs, M4 (QAKIRVRLSA), M5 (KIRVRLSA), and M6 (QKKIRVRLSA) with enhanced stability to natural degradation and antimicrobial activity against a large panel of gram-negative bacteria. The MICs of the most potent peptide, M6, were as low as 4 to 8 microg/ml against recent clinical isolates of multidrug-resistant Pseudomonas aeruginosa and members of the Enterobacteriaceae. The same dendrimeric peptides showed high stability to blood proteases, low hemolytic activity, and low cytotoxic effects on eukaryotic cells, making them promising candidates for the development of new antibacterial drugs.
Sezione di Biochimica, Dipartimento di Biologia Molecolare, Università degli Studi di Siena, Via Fiorentina 1, 53100 Siena, Italy. pinia@unisi.it
Alessandro
A
Pini
Andrea
A
Giuliani
Chiara
C
Falciani
Ylenia
Y
Runci
Claudia
C
Ricci
Barbara
B
Lelli
Monica
M
Malossi
Paolo
P
Neri
Gian Maria
GM
Rossolini
Luisa
L
Bracci
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004755:Enterobacteriaceae / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects
D000900:Anti-Bacterial Agents; D019151:Peptide Library; D010455:Peptides