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.
authors.affiliation: School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
authors.forename: Yifat
authors.initials: Y
authors.lastname: Berkov-Zrihen
authors.forename: Ido M
authors.initials: IM
authors.lastname: Herzog
authors.forename: Mark
authors.initials: M
authors.lastname: Feldman
authors.forename: Adar
authors.initials: A
authors.lastname: Sonn-Segev
authors.forename: Yael
authors.initials: Y
authors.lastname: Roichman
authors.forename: Micha
authors.initials: M
authors.lastname: Fridman
mesh_terms: D000478:Alkylation; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D010303:Paromomycin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017192:Skin Diseases, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D010303:Paromomycin