De novo design and in vivo activity of conformationally restrained antimicrobial arylamide foldamers.
The emergence of drug-resistant bacteria has compromised the use of many conventional antibiotics, leading to heightened interest in a variety of antimicrobial peptides. Although these peptides have attractive potential as antibiotics, their size, stability, tissue distribution, and toxicity have hampered attempts to harness these capabilities. To address such issues, we have developed small (molecular mass <1,000 Da) arylamide foldamers that mimic antimicrobial peptides. Hydrogen-bonded restraints in the arylamide template rigidify the conformation via hydrogen bond formation and increase activity toward Staphylococcus aureus and Escherichia coli. The designed foldamers are highly active against S. aureus in an animal model. These results demonstrate the application of foldamer templates as therapeutics.
Department of Biochemistry, University of Pennsylvania, 1009 Stellar Chance Laboratories, 36th and Hamilton Walk, Philadelphia, PA 19104, USA.
Sungwook
S
Choi
Andre
A
Isaacs
Dylan
D
Clements
Dahui
D
Liu
Hyemin
H
Kim
Richard W
RW
Scott
Jeffrey D
JD
Winkler
William F
WF
DeGrado
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D051379:Mice; D050296:Microbial Viability / Q000187:drug effects; D008958:Models, Molecular; D008968:Molecular Conformation
D000577:Amides; D000900:Anti-Bacterial Agents