Di-N-Methylation of Anti-Gram-Positive Aminoglycoside-Derived Membrane Disruptors Improves Antimicrobial Potency and Broadens Spectrum to Gram-Negative Bacteria

Raphael I. Benhamou, Pazit Shaul, Ido M. Herzog, Micha Fridman

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

The effect of di-N-methylation of bacterial membrane disruptors derived from aminoglycosides (AGs) on antimicrobial activity is reported. Di-N-methylation of cationic amphiphiles derived from several diversely structured AGs resulted in a significant increase in hydrophobicity compared to the parent compounds that improved their interactions with membrane lipids. The modification led to an enhancement in antibacterial activity and a broader antimicrobial spectrum. While the parent compounds were either modestly active or inactive against Gram-negative pathogens, the corresponding di-N-methylated compounds were potent against the tested Gram-negative as well as Gram-positive bacterial strains. The reported modification offers a robust strategy for the development of broad-spectrum membrane-disrupting antibiotics for topical use.

Original languageAmerican English
Pages (from-to)13617-13621
Number of pages5
JournalAngewandte Chemie - International Edition
Volume54
Issue number46
DOIs
StatePublished - 1 Nov 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Keywords

  • aminoglycosides
  • antibiotics
  • bacteria
  • cationic amphiphiles
  • membrane disruption

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