Pyrazole derived ultra-short antimicrobial peptidomimetics with potent anti-biofilm activity
| Autor: | Kun Cho, Jeong Kyu Bang, Eun Young Kim, Geul Bang, Pethaiah Gunasekaran, Soo-Jae Lee, Nam-Hyung Kim, Young Ho Jeon, Ganesan Rajasekaran, Eun Kyoung Ryu, Mija Ahn, Hyun-Ju Lee, Song Yub Shin, Jae-Kyung Hyun |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Lysis Peptidomimetic Peptide Microbial Sensitivity Tests Pyrazole Polymerase Chain Reaction 01 natural sciences Melittin Cell membrane 03 medical and health sciences chemistry.chemical_compound Anti-Infective Agents Microscopy Electron Transmission Drug Discovery medicine Humans Pharmacology chemistry.chemical_classification Bacteria Molecular Structure 010405 organic chemistry Chemistry Macrophages Organic Chemistry General Medicine Antimicrobial 0104 chemical sciences Amino acid 030104 developmental biology medicine.anatomical_structure Biochemistry Biofilms Pyrazoles Peptidomimetics Antimicrobial Cationic Peptides |
| Zdroj: | European Journal of Medicinal Chemistry. 125:551-564 |
| ISSN: | 0223-5234 |
| Popis: | In this study, we report on the first chemical synthesis of ultra-short pyrazole-arginine based antimicrobial peptidomimetics derived from the newly synthesized N-alkyl/aryl pyrazole amino acids. Through the systematic tuning of hydrophobicity, charge, and peptide length, we identified the shortest peptide Py11 with the most potent antimicrobial activity. Py11 displayed greater antimicrobial activity against antibiotic-resistant bacteria, including MRSA, MDRPA, and VREF, which was approximately 2-4 times higher than that of melittin. Besides its higher selectivity (therapeutic index) toward bacterial cells than LL-37, Py11 showed highly increased proteolytic stability against trypsin digestion and maintained its antimicrobial activity in the presence of physiological salts. Interestingly, Py11 exhibited higher anti-biofilm activity against MDRPA compared to LL-37. The results from fluorescence spectroscopy and transmission electron microscopy (TEM) suggested that Py11 kills bacterial cells possibly by integrity disruption damaging the cell membrane, leading to the cytosol leakage and eventual cell lysis. Furthermore, Py11 displayed significant anti-inflammatory (endotoxin-neutralizing) activity by inhibiting LPS-induced production of nitric oxide (NO) and TNF-α. Collectively, our results suggest that Py11 may serve as a model compound for the design of antimicrobial and antisepsis agents. |
| Databáze: | OpenAIRE |
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