Proline residue‐modified polycationic analogs of gramicidin S with high antibacterial activity against both Gram‐positive and Gram‐negative bacteria and low hemolytic activity*

Abstract

Novel polycationic analogs of the cyclic decapeptide antibiotic, gramicidin S, possessing NH(2), D/L-Phe-NH or L-Lys-NH groups at the 4alpha- or 4beta-positions of the L-Pro residues, were synthesized. While L-Pro(4alpha/beta-NH(2))-containing analogs exhibited much weaker antibacterial activity, the D/L-Phe and L-Lys-substituted analogs exhibited higher antibacterial activity against Gram-negative bacteria than the parent gramicidin S. All of these additional amino group-containing analogs showed substantially reduced toxicity against human blood cells.

Cryogenic Methods for the Spectroscopy of Large, Biomolecular Ions

“…Under physiological conditions, GS is doubly protonated, which is the pharmacologically active form. NMR and X-ray analyses have revealed an anti-parallel β-sheet structure in solution [152] and in crystals [153], respectively. This highly stable β-sheet makes it a benchmark for studying such structures in proteins.…”

Novel Cycloundecapeptides Related to Gramicidin S with Both High Antibiotic Activity and Low Hemolytic Activity

“…8) However, GS has high hemolytic activity, preventing its direct use in combating microbial resistance. 9) To find candidates with high antimicrobial and low hemolytic activities, many GS analogs of various ring sizes have been designed and synthesized. 3,4,10,11) However, syntheses of antimicrobially active analogues of GS having a disordered symmetry from C 2 have almost never been reported, because the stable, amphiphilic b-sheet structure of GS with C 2 symmetry is considered essential for its strong antibacterial activity.…”

Polycationic Gramicidin S Analogues with Both High Antibiotic Activity and Very Low Hemolytic Activity

“…[1][2][3] In order to find drug candidates with high antimicrobial activity and low hemolytic activity, many analogues of GS, TA and GR have been designed and synthesized. [2][3][4][5][6][7][8][9][10][11][12][13][14][15] For example, we reported in the studies of GR using a lysine-scanning method, which is replaced by Lys residue in place of each constituent amino acid residue of GR, that the substitution of Pro 5,5′ and D-Tyr 6,6′ residues of the natural product with a cationic amino acid results the significant increase of the therapeutic index. 17,18) Further, similar results were obtained in the studies of single substitution of Gln 6 of the natural TA with a cationic amino acid residue by Qin et al 10) However, the modifications of each constituent amino acid residue of GS with cationic amino acid residue have not been performed yet.…”

“…It has been proposed that the principal modes of the antibiotic actions result from an interaction of these antibiotics with the cell membrane of the target microorganisms. [2][3][4][5][6][7][8][9][10][11][12][13][14][15] In addition, so far, no resistance has been found for the antibiotics, because it requires significant alteration of the lipid composition of the cell membrane. 16) However, GS, TA and GR have the high hemolytic activity, preventing their direct use in combating the microbial resistance.…”

“…Gramicidin S (GS), [2][3][4][5][6][7][8] cyclo(-Val -) 2 are potent cyclopeptide antibiotics with the amphiphilic β-sheet conformation. It has been proposed that the principal modes of the antibiotic actions result from an interaction of these antibiotics with the cell membrane of the target microorganisms.…”