All d-Lysine Analogues of the Antimicrobial Peptide HPA3NT3-A2 Increased Serum Stability and without Drug Resistance

• Published in: International journal of molecular sciences Vol. 21; no. 16; p. 5632
• Main Authors: Lee, Jong-Kook, Park, Yoonkyung
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06.08.2020; MDPI
• Subjects: Amino Acid Sequence; Amino acids; Animals; Antibiotic resistance; Antibiotics; Antiinfectives and antibacterials; Antimicrobial activity; Antimicrobial agents; Antimicrobial Cationic Peptides - blood; Antimicrobial Cationic Peptides - chemical synthesis; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacology; antimicrobial peptide; Antimicrobial peptides; Bacteria; Bacterial infections; Calcium; Calcium ions; Cell Death - drug effects; Circular Dichroism; Cytotoxicity; d -enantiomer; Drug resistance; Drug Resistance, Bacterial - drug effects; drug-resistant bacteria; E coli; Enzymes; Erythrocytes; Erythrocytes - drug effects; Erythrocytes - metabolism; Escherichia coli; Escherichia coli - drug effects; Gram-positive bacteria; HaCaT Cells; Humans; Infectious diseases; Lysine; Lysine - analogs & derivatives; Magnesium; Mammals; Marine organisms; Microbial Sensitivity Tests; Peptides; physiological condition; Physiology; Proteins; Proteolysis; Proteolytic enzymes; Residues; Ribosomal protein L1; Sheep; sheep RBCs; Sheep red blood cells; Sodium; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus infections; Stereoisomerism; Toxicity; d-enantiomer; physiological condition; sheep RBCs; drug-resistant bacteria; antimicrobial peptide
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21165632

Novel antibiotic drugs are urgently needed because of the increase in drug-resistant bacteria. The use of antimicrobial peptides has been suggested to replace antibiotics as they have strong antimicrobial activity and can be extracted from living organisms such as insects, marine organisms, and mammals. HPA3NT3-A2 ([Ala ] HPA3NT3) is an antimicrobial peptide that is an analogue of the HP (2-20) peptide derived from ribosomal protein L1. Although this peptide was shown to have strong antimicrobial activity against drug-resistant bacteria, it also showed lower toxicity against sheep red blood cells (RBCs) and HaCaT cells compared to HPA3NT3. The l-Lys residues of HPA3NT3-A2 was substituted with d-Lys residues (HPA3NT3-A2D; [d-Lys ] HPA3NT3-A2) to prevent the cleavage of peptide bonds by proteolytic enzymes under physiological conditions. This peptide showed an increased half-life and maintained its antimicrobial activity in the serum against ( ) and ( ) (pathogen). Furthermore, the antimicrobial activity of HPA3NT3-A2D was not significantly affected in the presence of mono- or divalent ions (Na , Mg , Ca ). Finally, l- or d-HPA3NT3-A2 peptides exhibited the strongest antimicrobial activity against antibiotic-resistant bacteria and failed to induce resistance in after 12 passages.