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Biocompatibility, low toxicity and high selectivity towards bacterial cells has been the hallmark of peptide-based antibiotics. The innate immune system has been employing such molecular systems against invading pathogens as a successful defense strategy. In this study, we attempt to develop topologically constrained antimicrobial peptides with syndiotactic stereochemical arrangement, by incorporating L and D amino acids successively in its amino acid sequence. Acetylated versions of the designed peptides were also examined for its influence on bactericidal potency, against Gram-positive and Gram-negative bacteria. Syndiotactic stereochemical arrangement of the polypeptide main chain mimics stereochemistry of Gramicidin, a naturally occurring antimicrobial peptides. Gramicidin is a class of penta-deca-peptides isolated from soil bacteria Bacillus brevis, but their utility as antibiotic was limited to topical use due to high levels of hemotoxicity. Activity profiles of the four de novo designed peptide variants show higher specificity towards Gram-positive bacteria than Gram-negative variants, matching earlier reports on the therapeutic potential of gramicidin as a broad spectrum antibiotic. Significantly, our hemolytic assay confirms very low (<1%) levels of toxicity for the designed peptides unlike gramicidin. Earlier reports confirm that incorporation of D amino acids effectively negates the possibility of proteolytic degradation, thus pointing to the potential utility of de novo designed peptides with diversified stereochemistry as a promising new approach in the generation of novel antibiotic peptides. [ABSTRACT FROM AUTHOR]