Generation of analogs having potent antimicrobial and hemolytic activities with minimal changes from an inactive 16-residue peptide corresponding to the helical region of Staphylococcus aureus delta-toxin.

The delta-toxin is a 26-residue peptide from Staphylococcus aureus with the sequence formyl-MAQDIISTIGDLVKWIIDTVNKFTKK. NMR studies indicate that the segment IISTIGDLVKWIIDTV occurs in an alpha-helical conformation in the toxin. A synthetic peptide corresponding to this segment, although helical, did not exhibit hemolytic activity. Since charged residues like D and K are likely to modulate cytolytic activity, analogs of the 16-residue peptide were synthesized where D was systematically replaced by K. Analogs in which the first D and both Ds were replaced by K showed potent antimicrobial and hemolytic activities. The analog in which the second D was replaced by K was relatively less active. However, all the peptides showed an alpha-helical structure with similar helical content. The activities of the peptides were found to correlate directly with their ability to permeabilize model membranes. Thus, by minimal judicious replacement of charged amino acids, it should be possible to generate cytolytic peptides from short segments of peptide toxins.