Roles of Cyclic Structure and Dehydro-Form Amino Acid Residue in a Peptide Antibiotic1

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Abstract
Conformational analyses of viomycin and related compounds were performed by means of PMR and CD spectroscopic investigations in relation to their antimicrobial activities. PMR signals for some a-methines and methylenes in the sixteen-membered ring of viomycin or dihydroviomycin showed different chemical shifts and splitting patterns from those of broxoviomycin. The differences can be explained by the different shielding effects on these protons by their neighbouring amide carbonyls due to the rigid or non-rigid conformations of the sixteen membered ring. Measurements of temperature dependency in PMR signals and model investigations supported this view. The CD spectra of viomycin and related compounds, which were deduced to possess rigid conformations by PMR studies, showed a peak at 215 nm, whereas compounds which were assumed not to have a rigid conformation did not show this peak. Modifications of the double bond of the 3-ureidodehydroalanine residue resulted in a conformational change of the sixteen-membered ring together with inactivation or reduction in antimicrobial activity. Thus, the dehydro residue in viomycin may have an important role in maintaining the rigid conformation. It is suggested that the rigid conformation is an important factor in the potency of the antibiotic, and the cyclic structure in the antibiotic is assumed to assist in maintaining the conformation. A possible role of D-form amino acids in peptide antibiotics is also discussed.