title: Ceragenins: cholic acid-based mimics of antimicrobial peptides.
abstract: The prevalence of drug-resistant bacteria drives the quest for new antimicrobials, including those that are not expected to readily engender resistance. One option is to mimic Nature's most ubiquitous means of controlling bacterial growth, antimicrobial peptides, which have evolved over eons. In general, bacteria remain susceptible to these peptides. Human antimicrobial peptides play a central role in innate immunity, and deficiencies in these peptides have been tied to increased rates of infection. However, clinical use of antimicrobial peptides is hampered by issues of cost and stability. The development of nonpeptide mimics of antimicrobial peptides may provide the best of both worlds: a means of using the same mechanism chosen by Nature to control bacterial growth without the problems associated with peptide therapeutics. The ceragenins were developed to mimic the cationic, facially amphiphilic structures of most antimicrobial peptides. These compounds reproduce the required morphology using a bile-acid scaffolding and appended amine groups. The resulting compounds are actively bactericidal against both gram-positive and gram-negative organisms, including drug-resistant bacteria. This antimicrobial activity originates from selective association of the ceragenins with negatively charged bacterial membrane components. Association has been studied with synthetic models of bacterial membrane components, with bacterial lipopolysaccharide, with vesicles derived from bacterial phospholipids, and with whole cells. Comparisons of the antimicrobial activities of ceragenins and representative antimicrobial peptides suggest that these classes of compounds share a mechanism of action. Rapid membrane depolarization is caused by both classes as well as blebbing of bacterial membranes. Bacteria express the same genes in response to both classes of compounds. On the basis of the antibacterial activities of ceragenins and preliminary in vivo studies, we expect these compounds to find use in augmenting or replacing antimicrobial peptides in treating human disease.
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602, USA.
authors.forename: Xin-Zhong
authors.initials: XZ
authors.lastname: Lai
authors.forename: Yanshu
authors.initials: Y
authors.lastname: Feng
authors.forename: Jacob
authors.initials: J
authors.lastname: Pollard
authors.forename: Judy N
authors.initials: JN
authors.lastname: Chin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rybak
authors.forename: Robert
authors.initials: R
authors.lastname: Bucki
authors.forename: Raquel F
authors.initials: RF
authors.lastname: Epand
authors.forename: Richard M
authors.initials: RM
authors.lastname: Epand
authors.forename: Paul B
authors.initials: PB
authors.lastname: Savage
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D040761:Biomimetic Materials / Q000737:chemistry* / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D019826:Cholic Acid / Q000737:chemistry*; D015195:Drug Design; D004926:Escherichia coli / Q000648:ultrastructure; D006801:Humans; D050296:Microbial Viability / Q000187:drug effects; D016982:Micrococcus luteus / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D021381:Protein Transport; D013211:Staphylococcus aureus / Q000187:drug effects; D013256:Steroids / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D016328:NF-kappa B; D010455:Peptides; D013256:Steroids; D019826:Cholic Acid