Abstract
A new class of antimicrobial agents with lower rates of resistance and different targets is urgently needed because of the rapidly increasing resistance to classical antibiotics. Amphipathic cationic α-helical antimicrobial peptides (AMPs) represent such a class of compounds. In our previous studies, using a 26-residue de novo designed antimicrobial peptide, we proposed the concept of “specificity determinant(s)”: positively charged residue(s) in the center of the non-polar face of AMPs that could decrease hemolytic activity/toxicity but increase or maintain the same level of antimicrobial activity to increase dramatically the therapeutic index. In the current study, we used d-enantiomers of two AMPs, Piscidin 1 isolated from fish and dermaseptin S4 isolated from frog. We substituted different positions in the center of the hydrophobic face with one or two lysine residue(s) (one or two “specificity determinant(s)”). This simple modification not only maintained or improved antimicrobial activity against Gram-negative pathogens Acinetobacter baumannii (11 strains) and Pseudomonas aeruginosa (6 strains), but also dramatically decreased hemolytic activity of human red blood cells, as predicted. Therapeutic indices improved by 55-fold and 730-fold for piscidin 1 (I9K) and dermaseptin S4 (L7K, A14K), respectively, against A. baumannii. Similarly, the therapeutic indices improved 32-fold and 980-fold for piscidin 1 (I9K) and dermaseptin S4 (L7K, A14K), respectively, against P. aeruginosa.
Highlights
Emergence of antimicrobial resistance is becoming a very large public health threat and has been recognized by, amongst others, the World Health Organization [1], the U.S Congress Office of Technology Assessment [2] and the United Kingdom House of Lords [3]
The urgency to develop new classes of antimicrobial agents against Gram-negative pathogens Acinetobacter baumannii and Pseudomonas aeruginosa was demonstrated by the dramatic increases in the incidence of antibiotic-resistant species in a recent study in Mexico [4]
We developed the design concept of the ―specificity determinant‖ which refers to substituting positively charged residue(s) in the center of the non-polar face of amphipathic α-helical or cyclic β-sheet antimicrobial peptides to create selectivity between eukaryotic and prokaryotic membranes; that is, antimicrobial activity is maintained and hemolytic activity or cell toxicity to mammalian cells is decreased or eliminated
Summary
Emergence of antimicrobial resistance is becoming a very large public health threat and has been recognized by, amongst others, the World Health Organization [1], the U.S Congress Office of Technology Assessment [2] and the United Kingdom House of Lords [3]. It is widely believed that native AMPs lack specificity and might be too toxic (ability to lyse mammalian cells, normally expressed as hemolytic activity against human red blood cells) to be used for systemic treatment [14,15] To overcome this problem, we developed the design concept of the ―specificity determinant‖ which refers to substituting positively charged residue(s) in the center of the non-polar face of amphipathic α-helical or cyclic β-sheet antimicrobial peptides to create selectivity between eukaryotic and prokaryotic membranes; that is, antimicrobial activity is maintained and hemolytic activity or cell toxicity to mammalian cells is decreased or eliminated. Piscidin 1 has the highest biological activity in this family with broad-spectrum activity against antibiotic-resistant bacteria, filamentous fungi, yeasts, and viruses [28,31,32]; piscidin 1 is not selective for bacterial versus mammalian cells, and caused hemolysis of human red blood cells with a HC50 of 11~20 μM, within one hour at 37 °C [33,34]
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