Antimicrobial activity of histidine-rich peptides is dependent on acidic conditions.
Synthetic peptides composed of multiples of the consensus heparin-binding Cardin and Weintraub sequences AKKARA and ARKKAAKA are antimicrobial. Replacement of lysine and arginine by histidine in these peptides completely abrogates their antimicrobial and heparin-binding activities at neutral pH. However, the antibacterial activity against Gram-negative (Escherichia coli, Pseudomonas aeruginosa) and Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus) as well as the fungus Candida albicans, was restored at acidic conditions (pH 5.5). Fluorescence microscopy and FACS analysis showed that the binding of the histidine-rich peptides to E. coli and Candida was significantly enhanced at pH 5.5. Likewise, fluorescence studies for assessment of membrane permeation as well as electron microscopy analysis of peptide-treated bacteria, paired with studies of peptide effects on liposomes, demonstrated that the peptides induce membrane lysis only at acidic pH. No discernible hemolysis was noted for the histidine-rich peptides. Similar pH-dependent antimicrobial activities were demonstrated for peptides derived from histidine-rich and heparin-binding regions of human kininogen and histidine-rich glycoprotein. The results demonstrate that the presence of an acidic environment is an important regulator of the activity of histidine-rich antimicrobial peptides.
Kacprzyk
Lukasz
L
Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul Gronostajowa 7, 30-387, Kraków, Poland.
Rydengård
Victoria
V
Mörgelin
Matthias
M
Davoudi
Mina
M
Pasupuleti
Mukesh
M
Malmsten
Martin
M
Schmidtchen
Artur
A
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D002942:Circular Dichroism; D006493:Heparin / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008081:Liposomes; D008969:Molecular Sequence Data; D011506:Proteins / Q000737:chemistry / Q000494:pharmacology*; D000099053:Histidine-Rich Glycoprotein
D000900:Anti-Bacterial Agents; D008081:Liposomes; D011506:Proteins; D000099053:Histidine-Rich Glycoprotein; D006493:Heparin