title: Lipo-γ-AApeptides as a new class of potent and broad-spectrum antimicrobial agents.
abstract: There is increasing demand to develop antimicrobial peptides (AMPs) as next generation antibiotic agents, as they have the potential to circumvent emerging drug resistance against conventional antibiotic treatments. Non-natural antimicrobial peptidomimetics are an ideal example of this, as they have significant potency and in vivo stability. Here we report for the first time the design of lipidated γ-AApeptides as antimicrobial agents. These lipo-γ-AApeptides show potent broad-spectrum activities against fungi and a series of Gram-positive and Gram-negative bacteria, including clinically relevant pathogens that are resistant to most antibiotics. We have analyzed their structure-function relationship and antimicrobial mechanisms using membrane depolarization and fluorescent microscopy assays. Introduction of unsaturated lipid chain significantly decreases hemolytic activity and thereby increases the selectivity. Furthermore, a representative lipo-γ-AApeptide did not induce drug resistance in S. aureus, even after 17 rounds of passaging. These results suggest that the lipo-γ-AApeptides have bactericidal mechanisms analogous to those of AMPs and have strong potential as a new class of novel antibiotic therapeutics.
authors.affiliation: Department of Chemistry, CHE 205, University of South Florida, 4202 E. Fowler Avenue, Tampa, Florida 33620, USA.
authors.forename: Youhong
authors.initials: Y
authors.lastname: Niu
authors.forename: Shruti
authors.initials: S
authors.lastname: Padhee
authors.forename: Haifan
authors.initials: H
authors.lastname: Wu
authors.forename: Ge
authors.initials: G
authors.lastname: Bai
authors.forename: Qiao
authors.initials: Q
authors.lastname: Qiao
authors.forename: Yaogang
authors.initials: Y
authors.lastname: Hu
authors.forename: Lacey
authors.initials: L
authors.lastname: Harrington
authors.forename: Whittney N
authors.initials: WN
authors.lastname: Burda
authors.forename: Lindsey N
authors.initials: LN
authors.lastname: Shaw
authors.forename: Chuanhai
authors.initials: C
authors.lastname: Cao
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Cai
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005658:Fungi / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D055666:Lipopeptides / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D057786:Peptidomimetics / Q000494:pharmacology*
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D055666:Lipopeptides; D057786:Peptidomimetics