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Development of Therapeutic Gramicidin S Analogues Bearing Plastic β,γ-Diamino Acids.
- Source :
-
ChemMedChem [ChemMedChem] 2020 Jun 17; Vol. 15 (12), pp. 1089-1100. Date of Electronic Publication: 2020 May 20. - Publication Year :
- 2020
-
Abstract
- Gramicidin S (GS), one of the most widely investigated antimicrobial peptides (AMPs), is known for its robust antimicrobial activity. However, it is restricted to topical application due to undesired hemolytic activity. With the aim of obtaining nontoxic GS analogues, we describe herein a molecular approach in which the native GS β-turn region is replaced by synthetic β,γ-diamino acids (β,γ-DiAAs). Four β,γ-DiAA diastereomers were employed to mimic the β-turn structure to afford GS analogues GS3-6, which exhibit diminished hemolytic activity. A comparative structural study demonstrates that the (βR,γS)-DiAA is the most-stable β-turn mimic. To further improve the therapeutic index (e. g., high antibacterial activity and low hemolytic activity) and to extend the molecular diversity, GS5 and GS6 were used as structural scaffolds to introduce additional hydrophobic or hydrophilic groups. We show that GS6K, GS6F and GS display comparable antibacterial activity, and GS6K and GS6F have significantly decreased toxicity. Moreover, antibacterial mechanism studies suggest that GS6K kills bacteria mainly through the disruption of the membrane.<br /> (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Anti-Bacterial Agents chemical synthesis
Anti-Bacterial Agents toxicity
Bacteria drug effects
Cell Line
Cell Membrane drug effects
Erythrocytes drug effects
Gramicidin toxicity
Hemolysis drug effects
Humans
Microbial Sensitivity Tests
Stereoisomerism
Anti-Bacterial Agents pharmacology
Gramicidin analogs & derivatives
Gramicidin pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1860-7187
- Volume :
- 15
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- ChemMedChem
- Publication Type :
- Academic Journal
- Accession number :
- 32233075
- Full Text :
- https://doi.org/10.1002/cmdc.202000097