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Indolicidin (Ind) is a cationic antimicrobial peptide (AMP) derived from the granules of bovine neutrophils. It is a short, 13 amino acid peptide (ILPWKWPWWPWRR-NH2) that is amidated at the C-terminus and contains the highest proportion of Trp and Pro residues. Like many other AMPs, it exhibits a broad spectrum of antimicrobial activity against bacteria, fungi and protozoa. It has been shown that Ind adopts a disordered conformation in solution and a membrane-interacting structure containing coils and turns. However, Ind exhibits some toxicity to human erythrocytes and mouse T lymphocytes. In the present study, to investigate the effect of Lys-linked dimerization of Ind C-terminal hexapeptide (WWPWRRNH2) on prokaryotic selectivity, bactericidal mechanism and LPS-neutralizing activity and to develop a novel short AMP having prokaryotic selectivity and LPS-neutralizing activity, we synthesized a Lys-linked dimeric peptide (di-Ind-6) of Ind C-terminal hexapeptide (Ind-6) (Table 1). We examined the antimicrobial activity of the peptides against a representative set of bacterial strains, including three Gram-negative bacteria (Escherichia coli [KCTC 1682], Pseudomonas aeruginosa [KCTC 1637] and Salmonella typhimurium [KCTC 1926]) and three Gram-positive bacteria (Bacillus subtilis [KCTC 3068], Staphylococcus epidermidis [KCTC 1917] and Staphylococcus aureus [KCTC 1621]). The MIC values of the peptides are shown in Table 2. A Lys-linked dimeric peptide (di-Ind-6) displayed 2to 4-fold increased antimicrobial activity compared to monomeric peptide (Ind6). Furthermore, Di-Ind-6 displayed a 2-fold enhanced antimicrobial activity against Gram-negative bacteria as compare to Ind. Next, the cytotoxicity of the peptides to mammalian cells was determined by measuring their hemolytic activity toward human red blood cells (h-RBCs) Concentrationresponse curves for the hemolytic activity of the peptides are shown in Figure 1. For a quantitative measure of the hemolytic activity of the peptides, we introduced the hemolytic concentration (HC50) defined as the lowest peptide concentration that produces 50% hemolysis (Table 3). The HC50 value for Ind and di-Ind-6 was 160 μg/mL and 192 μg/mL, respectively. Di-Ind-6 was somewhat less hemolytic than Ind. In contrast, Ind-6 did not induce hemolysis even at the highest peptide concentration tested (200 μg/mL). The therapeutic potential of peptide antimicrobial drugs lies in their prokaryotic selectivity to effectively kill bacterial cells without exhibiting significant cytotoxicity toward mammalian cells such as human red blood cells. To determine prokaryotic selectivity of the peptides, we calculated their therapeutic index (TI) (Table 3). The TI is a widely employed parameter to represent the specificity of antimicrobial agents. The TI of the peptides is calculated as the ratio of the HC50 to GM (geometric mean of MICs against six selected Table 1. Amino acid sequences and calculated and observed molecular masses of the peptides

Prokaryotic Selectivity, Bactericidal Mechanism and LPS-neutralizing Activity of Lys-linked Dimeric Peptide of Indolicidin C-terminal Hexapeptide