We believe that a synthetic peptide rational design approach of small incremental changes in hydrophobicity/hydrophilicity, amphipathicity, helicity and stability of cationic antimicrobial peptides will enable rapid progress in development of new potential peptide antibiotics. Utilizing this approach, we modified an existing antimicrobial peptide (V_(681)) with excellent antimicrobial activity and strong hemolytic activity (a poor therapeutic index) by substituting single D- or L-amino acid residues in the center of the non-polar and polar face. We were able to optimize the specificity of the parent peptide V_(681) with significantly increased therapeutic indices for V13K_L of 89-fold and 17-fold against Gram-negative and Gram-positive bacteria, respectively, and for V13A_D of 42-fold and 23-fold against Gram-negative and Gram-positive organisms, respectively.
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