A novel, rationally designed, hybrid antimicrobial peptide, inspired by cathelicidin and aurein, exhibits membrane-active mechanisms against Pseudomonas aeruginosa
| Autor: | Warunee Hanpithakpong, Ratchaneewan Aunpad, Sangdao Somsri, Natthaporn Klubthawee, Poom Adisakwattana |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Lipopolysaccharides Erythrocytes Cell Survival medicine.medical_treatment Antimicrobial peptides lcsh:Medicine Peptide Plasma protein binding Microbial Sensitivity Tests medicine.disease_cause Microbiology Hemolysis Article Cathelicidin Cell Line 03 medical and health sciences Mice Microscopy Electron Transmission Antibiotics Cell Wall Cathelicidins medicine Animals Humans lcsh:Science chemistry.chemical_classification Multidisciplinary 030102 biochemistry & molecular biology Pseudomonas aeruginosa Antimicrobials lcsh:R Toll-Like Receptors Rational design Antimicrobial Anti-Bacterial Agents 030104 developmental biology Biochemistry chemistry lcsh:Q Antibacterial activity Antimicrobial Cationic Peptides Protein Binding |
| Zdroj: | Scientific Reports Scientific Reports, Vol 10, Iss 1, Pp 1-17 (2020) |
| ISSN: | 2045-2322 |
| Popis: | Antimicrobial peptides (AMPs) are promising alternatives to classical antibiotics for the treatment of drug-resistant infections. Due to their versatility and unlimited sequence space, AMPs can be rationally designed by modulating physicochemical determinants to favor desired biological parameters and turned into novel therapeutics. In this study, we utilized key structural and physicochemical parameters, in combination with rational engineering, to design novel short α-helical hybrid peptides inspired by the well-known natural peptides, cathelicidin and aurein. By comparing homologous sequences and abstracting the conserved residue type, sequence templates of cathelicidin (P0) and aurein (A0) were obtained. Two peptide derivatives, P7 and A3, were generated by amino acid substitution based on their residue composition and distribution. In order to enhance antimicrobial activity, a hybrid analog of P7A3 was designed. The results demonstrated that P7A3 had higher antibacterial activity than the parental peptides with unexpectedly high hemolytic activity. Strikingly, C-terminal truncation of hybrid peptides containing only the α-helical segment (PA-18) and shorter derivatives confer potent antimicrobial activity with reduced hemolytic activity in a length‐dependent manner. Among all, PA-13, showed remarkable broad-spectrum antibacterial activity, especially against Pseudomonas aeruginosa with no toxicity. PA-13 maintained antimicrobial activity in the presence of physiological salts and displayed rapid binding and penetration activity which resulted in membrane depolarization and permeabilization. Moreover, PA-13 showed an anti-inflammatory response via lipopolysaccharide (LPS) neutralization with dose-dependent, inhibiting, LPS-mediated Toll-like receptor activation. This study revealed the therapeutic potency of a novel hybrid peptide, and supports the use of rational design in development of new antibacterial agents. |
| Databáze: | OpenAIRE |
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