Chemical Derivatives of Gramicidin

Abstract

Summary

Gramicidin was treated with a number of reagents which were known, or could be shown to combine with, either its indole, or its hydroxyl groups, or both. The products were prepared and assayed in search of a water-soluble derivative of low hemolytic and high antibacterial activity. Formaldehyde had previously been shown to decrease selectively the hemolytic activity, but to render gramicidin only slightly less water-insoluble.

1. A glyoxylic acid derivative was obtained, the sodium salt of which was water-soluble. The product, however, retained most of the original hemolytic activity, and attempts to find experimental conditions under which the advantages of the glyoxylic and formaldehyde treatment could be combined were not successful.

2. An indole sulfamate of gramicidin was obtained with pyridine-chlorosulfonic acid, the salts of which were readily soluble in aqueous alcohol. The product showed somewhat greater decreases in hemolytic, than in antibacterial activity.

3. The succinic half esters of gramicidin and methylol gramicidin showed the greatest promise. The succinyl derivative of gramicidin, containing one succinyl group for each ethanolamine residue, gave a water-soluble sodium salt. Its hemolytic activity was slightly decreased and could be further lowered by subsequent formaldehyde treatment. Notwithstanding the in vitro hemolytic activity, the derivative appeared to be remarkably nontoxic by intravenous injection. The succinic anhydride derivative of methylol-gramicidin, containing one succinyl for each indole-methylol plus each original hydroxyl group, was lowered in all, but markedly more in hemolytic and toxic than in antibacterial activities. Its sodium salt was water-soluble even in the presence of other ions, but not very stable at neutrality.