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Pharmaceuticals 2014, 7(4), 366-391; doi:10.3390/ph7040366
Article

“Specificity Determinants” Improve Therapeutic Indices of Two Antimicrobial Peptides Piscidin 1 and Dermaseptin S4 Against the Gram-negative Pathogens Acinetobacter baumannii and Pseudomonas aeruginosa

1
, 2
, 2
 and 1,*
Received: 22 January 2014; in revised form: 12 March 2014 / Accepted: 13 March 2014 / Published: 25 March 2014
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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.
Keywords: Acinetobacter baumannii; antimicrobial peptides; Gram-negative pathogens; Pseudomonas aeruginosa; specificity determinant(s); temperature-profiling by RP-HPLC Acinetobacter baumannii; antimicrobial peptides; Gram-negative pathogens; Pseudomonas aeruginosa; specificity determinant(s); temperature-profiling by RP-HPLC
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Jiang, Z.; Vasil, A.I.; Vasil, M.L.; Hodges, R.S. “Specificity Determinants” Improve Therapeutic Indices of Two Antimicrobial Peptides Piscidin 1 and Dermaseptin S4 Against the Gram-negative Pathogens Acinetobacter baumannii and Pseudomonas aeruginosa. Pharmaceuticals 2014, 7, 366-391.

AMA Style

Jiang Z, Vasil AI, Vasil ML, Hodges RS. “Specificity Determinants” Improve Therapeutic Indices of Two Antimicrobial Peptides Piscidin 1 and Dermaseptin S4 Against the Gram-negative Pathogens Acinetobacter baumannii and Pseudomonas aeruginosa. Pharmaceuticals. 2014; 7(4):366-391.

Chicago/Turabian Style

Jiang, Ziqing; Vasil, Adriana I.; Vasil, Michael L.; Hodges, Robert S. 2014. "“Specificity Determinants” Improve Therapeutic Indices of Two Antimicrobial Peptides Piscidin 1 and Dermaseptin S4 Against the Gram-negative Pathogens Acinetobacter baumannii and Pseudomonas aeruginosa." Pharmaceuticals 7, no. 4: 366-391.



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