title: Helical cationic antimicrobial peptide length and its impact on membrane disruption.
abstract: Cationic antimicrobial peptides (CAMPs) are important elements of innate immunity in higher organisms, representing an ancient defense mechanism against pathogenic bacteria. These peptides exhibit broad-spectrum antimicrobial activities, utilizing mechanisms that involve targeting bacterial membranes. Recently, a 34-residue CAMP (NA-CATH) was identified in cDNA from the venom gland of the Chinese cobra (Naja atra). A semi-conserved 11-residue pattern observed in the NA-CATH sequence provided the basis for generating an 11-residue truncated peptide, ATRA-1A, and its corresponding D-peptide isomer. While the antimicrobial and biophysical properties of the ATRA-1A stereoisomers have been investigated, their modes of action remain unclear. More broadly, mechanistic differences that can arise when investigating minimal antimicrobial units within larger naturally occurring CAMPs have not been rigorously explored. Therefore, the studies reported here are focused on this question and the interactions of full-length NA-CATH and the truncated ATRA-1A isomers with bacterial membranes. The results of these studies indicate that in engineering the ATRA-1A isomers, the associated change in peptide length and charge dramatically impacts not only their antimicrobial effectiveness, but also the mechanism of action they employ relative to that of the full-length parent peptide NA-CATH. These insights are relevant to future efforts to develop shorter versions of larger naturally occurring CAMPs for potential therapeutic applications.
authors: Department of Chemistry and Biochemistry, George Mason University, 4400 University Dr., Fairfax, VA 22030, USA.
authors: Melanie L
authors: ML
authors: Juba
authors: Department of Chemistry and Biochemistry, George Mason University, 4400 University Dr., Fairfax, VA 22030, USA.
authors: Devin K
authors: DK
authors: Porter
authors: Department of Chemistry and Biochemistry, George Mason University, 4400 University Dr., Fairfax, VA 22030, USA; Material Measurement Laboratory, National Institute of Science and Technology, 100 Bureau Dr., Gaithersburg, MD 20899, USA.
authors: Elissa H
authors: EH
authors: Williams
authors: Department of Chemistry and Biochemistry, George Mason University, 4400 University Dr., Fairfax, VA 22030, USA.
authors: Carlos A
authors: CA
authors: Rodriguez
authors: School of Systems Biology, George Mason University, 10900 University Blvd., Manassas, VA 20110, USA.
authors: Stephanie M
authors: SM
authors: Barksdale
authors: Department of Chemistry and Biochemistry, George Mason University, 4400 University Dr., Fairfax, VA 22030, USA. Electronic address: bbishop1@gmu.edu.
authors: Barney M
authors: BM
authors: Bishop
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001409:Bacillus cereus / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D054804:Cathelicidins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D002463:Cell Membrane Permeability / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004546:Elapid Venoms / Q000737:chemistry; D004926:Escherichia coli / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D007700:Kinetics; D050296:Microbial Viability / Q000187:drug effects; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D054804:Cathelicidins; D004546:Elapid Venoms; D009842:Oligopeptides; D010446:Peptide Fragments
keywords: Antimicrobial peptides; Cathelicidins; Membrane depolarization; Membrane permeabilization; Scanning electron microscopy; Stereochemistry