title: Self-assembled cationic amphiphiles as antimicrobial peptides mimics: Role of hydrophobicity, linkage type, and assembly state.
abstract: Inspired by high promise using naturally occurring antimicrobial peptides (AMPs) to treat infections caused by antimicrobial-resistant bacteria, cationic amphiphiles (CAms) were strategically designed as synthetic mimics to overcome associated limitations, including high manufacture cost and low metabolic stability. CAms with facially amphiphilic conformation were expected to demonstrate membrane-lytic properties and thus reduce tendency of resistance development. By systematically tuning the hydrophobicity, CAms with optimized compositions exhibited potent broad-spectrum antimicrobial activity (with minimum inhibitory concentrations in low μg/mL range) as well as negligible hemolytic activity. Electron microscope images revealed the morphological and ultrastructure changes of bacterial membranes induced by CAm treatment and validated their membrane-disrupting mechanism. Additionally, an all-atom molecular dynamics simulation was employed to understand the CAm-membrane interaction on molecular level. This study shows that these CAms can serve as viable scaffolds for designing next generation of AMP mimics as antimicrobial alternatives to combat drug-resistant pathogens.
authors: Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, USA.
authors: Yingyue
authors: Y
authors: Zhang
authors: Department of Microbiology and Biochemistry, Rutgers University, New Brunswick, NJ, USA; Department of Microbiology, Veterinary College, Diyala University, Baqubah, Iraq.
authors: Ammar
authors: A
authors: Algburi
authors: Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, USA.
authors: Ning
authors: N
authors: Wang
authors: Office of Advanced Research Computing (OARC), Rutgers University, Piscataway, NJ, USA; Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA; Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA.
authors: Vladyslav
authors: V
authors: Kholodovych
authors: Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA.
authors: Drym O
authors: DO
authors: Oh
authors: School of Environmental and Biological Science, Rutgers University, New Brunswick, NJ, USA; Center for Digestive Health, NJ Institute for Food, Nutrition and Health, New Brunswick, NJ, USA.
authors: Michael
authors: M
authors: Chikindas
authors: Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, USA. Electronic address: keuhrich@rutgers.edu.
authors: Kathryn E
authors: KE
authors: Uhrich
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry*; D023181:Antimicrobial Cationic Peptides; D006461:Hemolysis; D057927:Hydrophobic and Hydrophilic Interactions; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides
keywords: Antimicrobial activity; Antimicrobial peptides; Membrane disruption; Self-assembly; Synthetic mimics