Abstract
We report the parallel synthesis of gramicidin S derivatives featuring backbone N-amino substituents. Analogues were prepared by incorporation of N-amino dipeptide subunits on solid support. Nine backbone-aminated macrocycles were evaluated for growth inhibitory activity against ESKAPE pathogens and hemolytic activity against human red blood cells. Diamination of the Orn residues in the β-strand region of gramicidin S was found to enhance broad-spectrum antimicrobial activity without a corresponding increase in hemolytic activity.
Keywords:
Amino acid; Antibiotic; Beta-sheet; Peptide; Peptidomimetic.
Copyright © 2020 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Acinetobacter baumannii / drug effects
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology*
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Dose-Response Relationship, Drug
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Enterobacter cloacae / drug effects
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Enterococcus faecium / drug effects
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Erythrocytes / drug effects*
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Gramicidin / chemical synthesis
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Gramicidin / chemistry
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Gramicidin / pharmacology*
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Humans
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Klebsiella pneumoniae / drug effects
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Microbial Sensitivity Tests
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Molecular Structure
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Pseudomonas aeruginosa / drug effects
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Staphylococcus aureus / drug effects
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Structure-Activity Relationship
Substances
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Anti-Bacterial Agents
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Gramicidin