title: Di-N-Methylation of Anti-Gram-Positive Aminoglycoside-Derived Membrane Disruptors Improves Antimicrobial Potency and Broadens Spectrum to Gram-Negative Bacteria.
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.
authors.affiliation: School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, 6997801 (Israel).
authors.forename: Raphael I
authors.initials: RI
authors.lastname: Benhamou
authors.affiliation: School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, 6997801 (Israel).
authors.forename: Pazit
authors.initials: P
authors.lastname: Shaul
authors.affiliation: School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, 6997801 (Israel).
authors.forename: Ido M
authors.initials: IM
authors.lastname: Herzog
authors.affiliation: School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, 6997801 (Israel). mfridman@post.tau.ac.il.
authors.forename: Micha
authors.initials: M
authors.lastname: Fridman
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000617:Aminoglycosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D008745:Methylation; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents
keywords: aminoglycosides; antibiotics; bacteria; cationic amphiphiles; membrane disruption