Structural correlates of antimicrobial efficacy in IL-8 and related human kinocidins.
Chemokines are small (8-12 kDa) effector proteins that potentiate leukocyte chemonavigation. Beyond this role, certain chemokines have direct antimicrobial activity against human pathogenic organisms; such molecules are termed kinocidins. The current investigation was designed to explore the structure-activity basis for direct microbicidal activity of kinocidins. Amino acid sequence and 3-dimensional analyses demonstrated these molecules to contain iterations of the conserved gamma-core motif found in broad classes of classical antimicrobial peptides. Representative CXC, CC and C cysteine-motif-group kinocidins were tested for antimicrobial activity versus human pathogenic bacteria and fungi. Results demonstrate that these molecules exert direct antimicrobial activity in vitro, including antibacterial activity of native IL-8 and MCP-1, and microbicidal activity of native IL-8. To define molecular determinants governing its antimicrobial activities, the IL-8 gamma-core (IL-8gamma) and alpha-helical (IL-8alpha) motifs were compared to native IL-8 for antimicrobial efficacy in vitro. Microbicidal activity recapitulating that of native IL-8 localized to the autonomous IL-8alpha motif in vitro, and demonstrated durable microbicidal activity in human blood and blood matrices ex vivo. These results offer new insights into the modular architecture, context-related deployment and function, and evolution of host defense molecules containing gamma-core motifs and microbicidal helices associated with antimicrobial activity.
Yount
Nannette Y
NY
Division of Infectious Diseases, LAC-Harbor UCLA Medical Center, Torrance, CA 90509, USA.
Waring
Alan J
AJ
Gank
Kimberly D
KD
Welch
William H
WH
Kupferwasser
Deborah
D
Yeaman
Michael R
MR
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects; D018925:Chemokines / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002942:Circular Dichroism; D015169:Colony Count, Microbial; D017124:Conserved Sequence; D003545:Cysteine / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D016209:Interleukin-8 / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000145:classification / Q000302:isolation & purification / Q000494:pharmacology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D012486:Salmonella typhimurium / Q000187:drug effects; D017386:Sequence Homology, Amino Acid; D013053:Spectrophotometry; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D018925:Chemokines; D016209:Interleukin-8; D010455:Peptides; D011994:Recombinant Proteins; D003545:Cysteine