title: Helical 1:1 α/Sulfono-γ-AA Heterogeneous Peptides with Antibacterial Activity.
abstract: As one of the greatest threats facing the 21st century, antibiotic resistance is now a major public health concern. Host-defense peptides (HDPs) offer an alternative approach to combat emerging multi-drug-resistant bacteria. It is known that helical HDPs such as magainin 2 and its analogs adopt cationic amphipathic conformations upon interaction with bacterial membranes, leading to membrane disruption and subsequent bacterial cell death. We have previously shown that amphipathic sulfono-γ-AApeptides could mimic magainin 2 and exhibit bactericidal activity. In this article, we demonstrate for the first time that amphipathic helical 1:1 α/sulfono-γ-AA heterogeneous peptides, in which regular amino acids and sulfono-γ-AApeptide building blocks are alternatively present in a 1:1 pattern, display potent antibacterial activity against both Gram-positive and Gram-negative bacterial pathogens. Small angle X-ray scattering (SAXS) suggests that the lead sequences adopt defined helical structures. The subsequent studies including fluorescence microscopy and time-kill experiments indicate that these hybrid peptides exert antimicrobial activity by mimicking the mechanism of HDPs. Our findings may lead to the development of HDP-mimicking antimicrobial peptidomimetics that combat drug-resistant bacterial pathogens. In addition, our results also demonstrate the effective design of a new class of helical foldamer, which could be employed to interrogate other important biological targets such as protein-protein interactions in the future.
authors.affiliation: Department of Chemistry, University of South Florida , 4202 East Fowler Avenue, Tampa, Florida 33620, United States.
authors.forename: Fengyu
authors.initials: F
authors.lastname: She
authors.affiliation: Department of Chemistry, University of South Florida , 4202 East Fowler Avenue, Tampa, Florida 33620, United States.
authors.forename: Alekhya
authors.initials: A
authors.lastname: Nimmagadda
authors.affiliation: Department of Chemistry, University of South Florida , 4202 East Fowler Avenue, Tampa, Florida 33620, United States.
authors.forename: Peng
authors.initials: P
authors.lastname: Teng
authors.affiliation: Department of Chemistry, University of South Florida , 4202 East Fowler Avenue, Tampa, Florida 33620, United States.
authors.forename: Ma
authors.initials: M
authors.lastname: Su
authors.affiliation: X-ray Science Division, Argonne National Laboratory , 9700 South Cass Avenue, Argonne, Illinois 60439, United States.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Zuo
authors.affiliation: Department of Chemistry, University of South Florida , 4202 East Fowler Avenue, Tampa, Florida 33620, United States.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Cai
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008856:Microscopy, Fluorescence; D008968:Molecular Conformation; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D057786:Peptidomimetics; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D010446:Peptide Fragments; D057786:Peptidomimetics; D013450:Sulfones