Dissociation of antimicrobial and hemolytic activities of gramicidin S through N-methylation modification Article

Li, Y, Bionda, N, Yongye, A et al. (2013). Dissociation of antimicrobial and hemolytic activities of gramicidin S through N-methylation modification . CHEMMEDCHEM, 8(11), 1865-1872. 10.1002/cmdc.201300232

cited authors

  • Li, Y; Bionda, N; Yongye, A; Geer, P; Stawikowski, M; Cudic, P; Martinez, K; Houghten, RA

authors

abstract

  • β-Sheet antimicrobial peptides (AMPs) are well recognized as promising candidates for the treatment of multidrug-resistant bacterial infections. To dissociate antimicrobial activity and hemolytic effect of b-sheet AMPs we hypothesize that N-methylation of the intramolecular hydrogen bond(s)-forming amides could improve their specificities for microbial cells over human erythrocytes. We utilized a model b-sheet antimicrobial peptide gramicidin S (GS) to study the N-methylation effects on the antimicrobial and hemolytic activities. We synthesized twelve N-methylated GS analogues by replacement of residues at the β-strand and β-turn regions with N-methyl amino acids and tested their antimicrobial and hemolytic activities. Our experiments showed that the HC50 values increased fivefold compared with that of GS when the internal hydrogen-bonded leucine residue was methylated. Neither hemolytic effect nor antimicrobial activity changed when proline alone was replaced with N-methylalanine in the b-turn region. However analogues containing N-methylleucine at β-strand and N-methylalanine at β-turn regions exhibited a fourfold increase in selectivity index compared to GS. We also examined the conformation of these N-methylated GS analogues using 1H NMR and circular dichroism (CD) spectroscopy in aqueous solution and visualized the backbone structures and residue orientations using molecular dynamics simulations. The results show that N-methylation of the internal hydrogen bond-forming amide affected the conformation backbone shape and side chain orientation of GS. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

publication date

  • November 1, 2013

published in

Digital Object Identifier (DOI)

start page

  • 1865

end page

  • 1872

volume

  • 8

issue

  • 11