Diastereoisomeric analogues of gramicidin S: structure, biological activity and interaction with lipid bilayers

Abstract

Analogues of a structurally equivalent version of theantimicrobial decameric cyclic peptide gramicidin S, GS10 [cyclo-(Val-Lys-Leu-d-Tyr-Pro)(2)], were designed to study theeffect of distortion in the beta-sheet/beta-turn structure of thecyclic peptide on its biological activity. In one approach, thehydrophobic nature of GS10 was conserved, and single amino acids in itsbackbone were replaced systematically with their correspondingenantiomers to give five diastereoisomeric analogues. In a relatedapproach, a more basic and hydrophilic analogue of GS10 [cyclo-(Lys-Val-Lys-d-Tyr-Pro(5)-Lys-Leu-Lys-d-Tyr-Pro(10))], together with two of itsmonosubstituted diastereoisomeric analogues (featuring d-Lys(1) or d-Val(2) respectively), weresynthesized. CD spectra were measured in a variety of environments,i.e. aqueous, aqueous trifluoroethanol and those containing SDSmicelles or phospholipid vesicles. In comparison with GS10 spectra, CDspectra of both groups of analogues in these environments exhibitedstructural distortion. Moreover, compared with GS10, antimicrobial andhaemolytic activities of the analogues were drastically decreased, implying the existence of a threshold minimum amphipathicity foreffective biological activity. However, in both groups of analogues,there was a correlation between amphipathicity and antimicrobial andhaemolytic activities. In the second group of analogues, bothelectrostatic and hydrophobic factors were related to theirantimicrobial and haemolytic activities. In order to gain an insightinto the nature of the biological activity of the two classes of cyclicpeptides, the relationship of their structure to interaction with lipidmembranes, and the implied mechanisms, were analysed in some detail inthe present study.

Structure-Activity Relationships of Diastereomeric Lysine Ring Size Analogs of the Antimicrobial Peptide Gramicidin S

“…Finally, the molar ellipticities of GS14dK 4 and GS14dK 11 are generally comparable in magnitude as are those of GS14dK 2 and GS14dK 9 , indicating that the conformational distortions caused by enantiomeric inversions of the K 4 and K 11 residues of the GS14 molecule are comparable but different from those caused by enantiomeric inversions of the K 2 and K 9 residues. Thus, despite the inequivalent structures of the four single-substitution derivatives, there are some structural similarities between GS14dK 11 and GS14dK 4 and between GS14dK 2 and GS14dK 9 . Fig.…”

“…Gramicidin S (GS) 1 is a cyclic decapeptide that exhibits strong antibiotic activity against a broad spectrum of Gramnegative and Gram-positive bacteria and against several pathogenic fungi (3)(4)(5)(6)(7)(8)(9). Numerous studies by us and others have shown that disruption of the barrier properties of cell membranes is the basis of the antimicrobial and hemolytic properties of GS (3,4,10).…”

Damage of the Bacterial Cell Envelope by Antimicrobial Peptides Gramicidin S and PGLa as Revealed by Transmission and Scanning Electron Microscopy

“…It is particularly active against Gram-positive bacteria and, to a lesser extent, also against Gram-negative ones (23), Mycoplasma species (41), fungi (26), and viruses (9). The MIC against different E. coli strains lies between 3 and 12.5 g/ml, and that against S. aureus lies at 1.5 g/ml (26).…”

“…The MIC against different E. coli strains lies between 3 and 12.5 g/ml, and that against S. aureus lies at 1.5 g/ml (26). Since GS shows hemolytic activity at 12 to 40 g/ml (23,27), its intravenous use is restricted, but local application is successful for the treatment of acute subcutaneous inflammation, infected wounds, and burns (15). The symmetric cyclic ␤-stranded backbone is amphiphilic due to two basic ornithine side chains on one face and hydrophobic residues on the other (31).…”

Structure and Association of Human Lactoferrin Peptides withEscherichia coliLipopolysaccharide

“…Although certain peptide structural groups have been noted, including amphipathic ␣ helices, ␤ structures, extended structures, and loops, no overall conservation of amino acids exists (3,12). Furthermore, peptides can fold in such a way as to segregate the charged or hydrophilic portions from the hydrophobic residues, thus permitting these highly charged peptides to interact with bacterial membranes (16). Structural studies have determined that some antimicrobial peptides that do not have a disulfide bond tend to be irregular in solution, forming a structure upon binding to bacterial membranes (1,7,24).…”