Di-alkylated paromomycin derivatives: Targeting the membranes of Gram positive pathogens that cause skin infections

A collection of paromomycin-based di-alkylated cationic amphiphiles differing in the lengths of their aliphatic chain residues were designed, synthesized, and evaluated against 14 Gram positive pathogens that are known to cause skin infections. Paromomycin derivatives that were di-alkylated with C7...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2013-06, Vol.21 (12), p.3624-3631
Main Authors: Berkov-Zrihen, Yifat, Herzog, Ido M., Feldman, Mark, Sonn-Segev, Adar, Roichman, Yael, Fridman, Micha
Format: Article
Language:English
Subjects:
Alkylation
aminoglycosides
Amphiphilic aminoglycosides
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
anti-infective properties
Cationic amphiphiles
chemistry
Dose-Response Relationship, Drug
erythrocytes
Gram-Positive Bacteria - drug effects
gramicidin
Hemolysis
Membrane-targeting antibiotics
Microbial Sensitivity Tests
Molecular Conformation
Paromomycin - chemical synthesis
Paromomycin - chemistry
Paromomycin - pharmacology
pathogens
scanning electron microscopy
Skin Diseases, Bacterial - drug therapy
Skin Diseases, Bacterial - microbiology
Skin infection causing bacteria
Structure-Activity Relationship
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Summary:A collection of paromomycin-based di-alkylated cationic amphiphiles differing in the lengths of their aliphatic chain residues were designed, synthesized, and evaluated against 14 Gram positive pathogens that are known to cause skin infections. Paromomycin derivatives that were di-alkylated with C7 and C8 linear aliphatic chains had improved antimicrobial activities relative to the parent aminoglycoside as well as to the clinically used membrane-targeting antibiotic gramicidin D; several novel derivatives were at least 16-fold more potent than the parent aminoglycoside paromomycin. Comparison between a di-alkylated and a mono-alkylated paromomycin indicated that the di-alkylation strategy leads to both an improvement in antimicrobial activity and to a dramatic reduction in undesired red blood cell hemolysis caused by many aminoglycoside-based cationic amphiphiles. Scanning electron microscopy provided evidence for cell surface damage by the reported di-alkylated paromomycins.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2013.03.046