De nova generation of cationic antimicrobial peptides: Influence of length and tryptophan substitution on antimicrobial activity

被引:223
作者
Deslouches, B
Phadke, SM
Lazarevic, V
Cascio, M
Islam, K
Montelaro, RC
Mietzner, TA
机构
[1] Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA
[2] Childrens Hosp Pittsburgh, Dept Pediat, Pittsburgh, PA 15213 USA
关键词
D O I
10.1128/AAC.49.1.316-322.2005
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Comparison of human immunodeficiency virus lentiviral lytic peptide 1 with other host-derived peptides indicates that antimicrobial properties of membrane-active peptides are markedly influenced by their cationic, hydrophobic, and amphipathic properties. Many common themes, such as Arg composition of the cationic face of an amphipathic helix and the importance of maintaining the hydrophobic face, have been deduced from these observations. These studies suggest that a peptide with these structural properties can be derived de novo by using only a few strategically positioned amino acids. However, the effects of length and helicity on antimicrobial activity and selectivity have not been objectively evaluated in the context of this motif. To address these structure-function issues, multimers of a 12-residue lytic base unit (LBU) peptide composed only of Arg and Val residues aligned to form idealized amphipathic helices were designed. Bacterial killing assays and circular dichroism analyses reveal a strong correlation between antibacterial activity, peptide length, and propensity to form a helix in solvent mimicking the environment of a membrane. Increasing peptide length beyond two LBUs (24-residue peptides) resulted in no appreciable increase in antimicrobial activity. Derivatives (WLBU) of the LBU series were further engineered by substituting Trp residues in the hydrophobic domains. The 24-residue WLBU2 peptide was active at physiologic NaCl concentrations against Staphylococcus aureus and mucoid and nonmucoid strains of Pseudomonas aeruginosa. Further, WLBU2 displayed the highest antibacterial selectivity of all peptides evaluated in the present study by using a coculture model of P. aeruginosa and primary human skin fibroblasts. These findings provide fundamental information toward the de novo design of an antimicrobial peptide useful for the management of infectious diseases.
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页码:316 / 322
页数:7
相关论文
共 36 条
  • [1] EVALUATION OF SECONDARY STRUCTURE OF PROTEINS FROM UV CIRCULAR-DICHROISM SPECTRA USING AN UNSUPERVISED LEARNING NEURAL-NETWORK
    ANDRADE, MA
    CHACON, P
    MERELO, JJ
    MORAN, F
    [J]. PROTEIN ENGINEERING, 1993, 6 (04): : 383 - 390
  • [2] Interactions of α-helices with lipid bilayers:: a review of simulation studies
    Biggin, PC
    Sansom, MSP
    [J]. BIOPHYSICAL CHEMISTRY, 1999, 76 (03) : 161 - 183
  • [3] CHEN CF, 1990, CHIN MED J TAIPEI, V46, P7
  • [4] Oxyopinins, large amphipathic peptides isolated from the venom of the wolf spider Oxyopes kitabensis with cytolytic properties and positive insecticidal cooperativity with spider neurotoxins
    Corzo, G
    Villegas, E
    Gómez-Lagunas, F
    Possani, LD
    Belokoneva, OS
    Nakajima, T
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (26) : 23627 - 23637
  • [5] Cuervo J H, 1988, Pept Res, V1, P81
  • [6] HYDROPHOBICITY AND AMPHIPHILICITY IN PROTEIN-STRUCTURE
    EISENBERG, D
    WILCOX, W
    MCLACHLAN, AD
    [J]. JOURNAL OF CELLULAR BIOCHEMISTRY, 1986, 31 (01) : 11 - 17
  • [7] FONTENOT J D, 1991, Peptide Research, V4, P19
  • [8] AN IMPROVED MTT ASSAY USING THE ELECTRON-COUPLING AGENT MENADIONE
    GARN, H
    KRAUSE, H
    ENZMANN, V
    DROSSLER, K
    [J]. JOURNAL OF IMMUNOLOGICAL METHODS, 1994, 168 (02) : 253 - 256
  • [9] Cationic peptides: a new source of antibiotics
    Hancock, REW
    Lehrer, R
    [J]. TRENDS IN BIOTECHNOLOGY, 1998, 16 (02) : 82 - 88
  • [10] Hancock REW, 1997, J MED MICROBIOL, V46, P1