Modular determinants of antimicrobial activity in platelet factor-4 family kinocidins.
Mammalian platelets contain an array of antimicrobial peptides, termed platelet microbicidal proteins (PMPs). Human and rabbit PMPs include known chemokines, such as platelet factor-4 (hPF-4); PMP-1 is the rabbit orthologue of hPF-4. Chemokines that also exert direct antimicrobial activity have been termed kinocidins. A consensus peptide domain library representing mammalian PF-4 family members was analyzed to define structural domains contributing to antimicrobial activity against a panel of human pathogens. Secondary conformations were assessed by circular dichroism spectrometry, and molecular modeling was employed to investigate structural correlates of antimicrobial efficacy. Antimicrobial activity against isogenic peptide-susceptible or -resistant Staphylococcus aureus, Salmonella typhimurium, and Candida albicans strain pairs mapped to the C-terminal hemimer (38-74) and modular domains thereof (49-63 and 60-74). Increasing electrostatic charge and steric bulk were general correlates of efficacy. Structural data corroborated spatial distribution of charge, steric bulk and putative secondary structure with organism-specific efficacy. Microbicidal efficacies of the cPMP antimicrobial hemimer and C-terminal peptide (60-74) were retained in a complex human-blood biomatrix assay. Collectively, these results suggest that modular determinants arising from structural components acting independently and cooperatively govern the antimicrobial functions of PF-4 family kinocidins against specific target pathogens.
Yeaman
Michael R
MR
Division of Infectious Diseases, LAC-Harbor UCLA Medical Center, Torrance, CA 90509, USA. MRYeaman@ucla.edu
Yount
Nannette Y
NY
Waring
Alan J
AJ
Gank
Kimberly D
KD
Kupferwasser
Deborah
D
Wiese
Robert
R
Bayer
Arnold S
AS
Welch
William H
WH
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001792:Blood Platelets / Q000737:chemistry; D002176:Candida albicans / Q000187:drug effects; D018925:Chemokines / Q000737:chemistry* / Q000494:pharmacology*; D002942:Circular Dichroism; D015169:Colony Count, Microbial; D004305:Dose-Response Relationship, Drug; D006801:Humans; D013058:Mass Spectrometry; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010978:Platelet Factor 4 / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012486:Salmonella typhimurium / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects; D055672:Static Electricity; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D018925:Chemokines; D010978:Platelet Factor 4