title: Context mediates antimicrobial efficacy of kinocidin congener peptide RP-1.
abstract: Structure-mechanism relationships are key determinants of host defense peptide efficacy. These relationships are influenced by anatomic, physiologic and microbiologic contexts. Structure-mechanism correlates were assessed for the synthetic peptide RP-1, modeled on microbicidal domains of platelet kinocidins. Antimicrobial efficacies and mechanisms of action against susceptible ((S)) or resistant ((R)) Salmonella typhimurium (ST), Staphylococcus aureus (SA), and Candida albicans (CA) strain pairs were studied at pH 7.5 and 5.5. Although RP-1 was active against all study organisms, it exhibited greater efficacy against bacteria at pH 7.5, but greater efficacy against CA at pH 5.5. RP-1 de-energized SA and CA, but caused hyperpolarization of ST in both pH conditions. However, RP-1 permeabilized ST(S) and CA strains at both pH, whereas permeabilization was modest for ST(R) or SA strain at either pH. Biochemical analysis, molecular modeling, and FTIR spectroscopy data revealed that RP-1 has indistinguishable net charge and backbone trajectories at pH 5.5 and 7.5. Yet, concordant with organism-specific efficacy, surface plasmon resonance, and FTIR, molecular dynamics revealed modest helical order increases but greater RP-1 avidity and penetration of bacterial than eukaryotic lipid systems, particularly at pH 7.5. The present findings suggest that pH- and target-cell lipid contexts influence selective antimicrobial efficacy and mechanisms of RP-1 action. These findings offer new insights into selective antimicrobial efficacy and context-specificity of antimicrobial peptides in host defense, and support design strategies for potent anti-infective peptides with minimal concomitant cytotoxicity.
authors.affiliation: Division of Infectious Diseases, Los Angeles County-Harbor University of California Los Angeles Medical Center, Torrance, California, United States of America.
authors.forename: Nannette Y
authors.initials: NY
authors.lastname: Yount
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Cohen
authors.forename: Deborah
authors.initials: D
authors.lastname: Kupferwasser
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Waring
authors.forename: Piotr
authors.initials: P
authors.lastname: Ruchala
authors.forename: Shantanu
authors.initials: S
authors.lastname: Sharma
authors.forename: Karlman
authors.initials: K
authors.lastname: Wasserman
authors.forename: Chun-Ling
authors.initials: CL
authors.lastname: Jung
authors.forename: Michael R
authors.initials: MR
authors.lastname: Yeaman
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D012486:Salmonella typhimurium / Q000187:drug effects; D017550:Spectroscopy, Fourier Transform Infrared; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; C541455:RP-1 peptide
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