title: Synthesis of cationic antimicrobial β(2,2)-amino acid derivatives with potential for oral administration.
abstract: We have prepared a series of highly potent achiral cationic β(2,2)-amino acid derivatives that fulfill the Lipinski's rule of five and that contain the basic structural requirements of short cationic antimicrobial peptides. Highest antimicrobial potency was observed for one of the smallest β(2,2)-amino acid derivatives (M(w) 423.6) exhibiting a MIC of 3.8 μM against methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and Staphylococcus aureus, and 7.7 μM against Escherichia coli. The β(2,2)-amino acid derivatives were shown to have similar absorption properties as several commercially available drugs, and the results implied a resembling membrane disrupting mechanism of action as reported for much larger cationic antimicrobial peptides. By their high potency, nontoxicity, absorption properties, and ease of synthesis, the β(2,2)-amino acid derivatives demonstrate a way to modify a vastly investigated class of cationic antimicrobial peptides into small drug-like molecules with high commercial potential.
authors.affiliation: Department of Pharmacy, Faculty of Health Sciences, University of Tromsø, N-9037 Tromsø, Norway.
authors.forename: Terkel
authors.initials: T
authors.lastname: Hansen
authors.forename: Dominik
authors.initials: D
authors.lastname: Ausbacher
authors.forename: Gøril E
authors.initials: GE
authors.lastname: Flaten
authors.forename: Martina
authors.initials: M
authors.lastname: Havelkova
authors.forename: Morten B
authors.initials: MB
authors.lastname: Strøm
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D006461:Hemolysis; D006801:Humans; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D010539:Permeability; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects; D013212:Staphylococcus epidermidis / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides