This paper reports a study of the chemistry of valinomycin, enniatins and related membrane-active depsipeptides that increase alkali metal ion permeability of model and biological membranes. The antimicrobial activity of these compounds and their effect on membranes has been correlated with their cation-complexing ability. The complexing reaction has been studied by spectropolarimetric and conductimetric methods. Nuclear magnetic resonance, optical rotatory dispersion, and infrared spectrophotometric studies have revealed the coexistence of conformers of the cyclodepsipeptides in solution and have led to elucidation of the spatial structure of valinomycin, enniatin B and their K(+) complexes. The effect of the conformational properties of the cyclodepsipeptides on their complexation efficiency and selectivity, surface-active properties and behavior towards phospholipid monolayers, bimolecular phospholipid membranes and a number of biological membrane systems has been ascertained. The studies have clearly shown the feasibility of using cyclodepsipeptides with predetermined structural and conformational parameters as chemical tools for membrane studies. it is suggested that the principle of conformation-dependent cation binding through iondipole interactions may possibly lie at the basis of the mode of action of systems governing the natural ion permeability in biological membranes.
The ability of enniatins to bind alkali metal, alkaline earth metal and certain transition metal ions in solution has been investigated. The complexes have been shown to form in 1:1, 2:1 and 3:2 macrocycle:cation ratios; their stability constants have been determined, and the conditions favoring their formation have been established. The enniatins were shown to be complexones of very wide spectrum, displaying low metal ion selectivity in alcoholic solutions.
Two basic spatial forms, the non‐symmetric N3 form (in nonpolar solvents) and the symmetric P form (in polar solvents) have been disclosed and proposals made as to their conformational parameters. The molecular structure of the enniatin complexes has been established. Independent of the complexed ion species, of the complex stoichiometry, or of the type of solvent, the enniatin backbone of the complex is in the P form. In the 1:1 complexes, the ion is accommodated in the molecular cavity, forming iondipole bonds with all the amide and ester carbonyls. The depsipeptide chain of the enniatins is flexible, permitting “adaptation” of the complexone to the size of the ion, and thus explaining the low selectivity of these complexones. In the 2:1 and 3:2 complexes the cation is sandwiched in between two molecules of the antibiotic at the symmetry axis and interacts mainly with the N‐methylamide carbonyls. In these “sandwich” complexes the cation is much better screened from the anion and solvent than in the equimolar complexes and is highly soluble in organic solvents.
The data presented here may serve as basis for interpreting the dependence between the structure, metal complexing behavior and membrane‐affecting properties in the series of the naturally occurring enniatin ionophores and their synthetic analogs.
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