De Novo Designed Amphipathic α-Helical Antimicrobial Peptides Incorporating Dab and Dap Residues on the Polar Face To Treat the Gram-Negative Pathogen, Acinetobacter baumannii

We have designed de novo and synthesized ten 26-residue D-conformation amphipathic alpha-helical cationic antimicrobial peptides (AMPs), seven with specificity determinants, which provide specificity for prokaryotic cells over eukaryotic cells. The ten AMPs contain five or six positively charged residues (D-Arg, D-Lys, n-Orn, L-Dab, or L-Dap) on the polar face to understand their role in hemolytic activity against human red blood cells and antimicrobial activity against seven Acinetobacter baumannii strains, resistant to polymyxin B and colistin, and 20 A. baumannii worldwide isolates from 2016 and 2017 with antibiotic resistance to 18 different antibiotics. AMPs with specificity determinants and with L-Dab and L-Dap residues on the polar face have essentially no hemolytic activity at 1000 mu g/mL (380 mu M), showing for the first time the importance of these unusual amino acid residues in solving long-standing hemolysis issues of AMPs. Specificity determinants maintained excellent antimicrobial activity in the presence of human sera.