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Antimicrobial Agents and Chemotherapy, January 2005, p. 316-322, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.316-322.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

De Novo Generation of Cationic Antimicrobial Peptides: Influence of Length and Tryptophan Substitution on Antimicrobial Activity

Berthony Deslouches,1 Shruti M. Phadke,2 Vanja Lazarevic,1 Michael Cascio,1 Kazi Islam,1 Ronald C. Montelaro,1 and Timothy A. Mietzner1*

Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine,1 Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania2

Received 4 April 2004/ Returned for modification 6 June 2004/ Accepted 4 September 2004

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.

* Corresponding author. Mailing address: Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Lothrop St., Pittsburgh, PA 15261. Phone: (412) 648-9244. Fax: (412) 624-1401. E-mail: mietzner{at}pitt.edu.

Antimicrobial Agents and Chemotherapy, January 2005, p. 316-322, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.316-322.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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