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Antimicrobial peptides (AMPs) are widely distributed in nature, generally have broad-spectrum activity and represent a promising class of new antimicrobial agents. However, it is widely accepted that native AMPs lack specificity and may be too toxic (ability to lyse mammalian cells, normally expressed as hemolytic activity against human red blood cells) to be used for systemic treatment [1,2]. To overcome this problem, we developed the design concept of “specificity determinants” which refers to substituting positively charged residue(s) in the center of the non-polar face of amphipathic cyclic β-sheet [3,4] or amphipathic α-helical AMPs [5] to create selectivity between eukaryotic and prokaryotic membranes; that is, antimicrobial activity is improved or maintained and hemolytic activity or cell toxicity to mammalian cells is decreased or eliminated. We showed that a single valine to lysine substitution in the center of the non-polar face of an AMP dramatically reduced toxicity and increased the therapeutic index [5-7]. The question arose could we take such a broad spectrum AMP in the all-D conformation and use a rational design approach to enhance further the biological properties if the focus was to develop a better Gram-negative AMP rather than maintain broad-spectrum activity. Our final AMP had a 746fold improvement (i.e., decrease) in its hemolytic activity, improved antimicrobial activity and improved therapeutic indices by 1305-fold and 895-fold against Acinetobacter baumannii and Pseudomonas aeruginosa, respectively [7]. We applied this design concept to native AMPs, piscidin 1 (isolated from mast cells of hybrid striped bass Morone saxatilis male × Morone chrysops female) and dermaseptin S4 (isolated from the skin of tree-dwelling, South American frogs of the Phyllomedusa species), where substitution of one or two lysine residues at different positions in their non-polar faces enhanced or maintained Gram-negative activity, dramatically decreased hemolytic activity and significantly improved the therapeutic indices (55-fold and 730-fold for D-piscidin 1 I9K and D-dermaseptin S4 L7K, A14K against A. baumannii, respectively) [8]. In the current study, we used the above 2 native AMPs and tested their activity against 2 different pathogens: 11 and 20 diverse clinical isolates of A. baumannii, and Staphylococcus aureus (12 Methicillin-sensitive S. aureus strains and 8 Methicillin/Oxacillin-resistant S. aureus strains), respectively. We showed that substitution of “specificity determinant(s)” in broad spectrum AMPs, encode selectivity for Gram-negative pathogens and simultaneously remove both Gram-positive activity and hemolytic activity of these 2 diverse amphipathic α-helical AMPs which differ dramatically in amino acid composition, net positive charge and amphipathicity, showing generality of our approach.

Design of New Antimicrobial Peptides (AMPs) with “Specificity Determinants” that Encode Selectivity for Gram Negative Pathogens and Remove Both Gram-Positive Activity and Hemolytic Activity from Broad-spectrum AMPs