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

Yifat Berkov-Zrihen; Ido M. Herzog; Mark Feldman; Adar Sonn-Segev; Yael Roichman; Micha Fridman

doi:10.1016/j.bmc.2013.03.046

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

Yifat Berkov-Zrihen, Ido M. Herzog, Mark Feldman, Adar Sonn-Segev, Yael Roichman, Micha Fridman^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	3624-3631
Number of pages	8
Journal	Bioorganic and Medicinal Chemistry
Volume	21
Issue number	12
DOIs	https://doi.org/10.1016/j.bmc.2013.03.046
State	Published - 15 Jun 2013
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by the FP7-PEOPLE-2009-RG Marie Curie Action: Reintegration Grants (Grant 246673). We thank Professors Itzhak Ofek, Dani Cohen (Tel Aviv University), and Doron Steinberg (The Hebrew University of Jerusalem) for the gift of bacterial strains. We thank Anat Eldar-Boock from the group of Professor Ronit Satchi-Fainaro (Tel Aviv University) for her help with the hemolysis assays.

Keywords

Amphiphilic aminoglycosides
Cationic amphiphiles
Hemolysis
Membrane-targeting antibiotics
Skin infection causing bacteria

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

abstract = "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.",

keywords = "Amphiphilic aminoglycosides, Cationic amphiphiles, Hemolysis, Membrane-targeting antibiotics, Skin infection causing bacteria",

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note = "Funding Information: This work was supported by the FP7-PEOPLE-2009-RG Marie Curie Action: Reintegration Grants (Grant 246673). We thank Professors Itzhak Ofek, Dani Cohen (Tel Aviv University), and Doron Steinberg (The Hebrew University of Jerusalem) for the gift of bacterial strains. We thank Anat Eldar-Boock from the group of Professor Ronit Satchi-Fainaro (Tel Aviv University) for her help with the hemolysis assays. ",

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

Abstract

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Keywords

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