Structural features determining the haemolytic activity of vacidin A derivatives

The haemolytic activity of aromatic heptaene antifungal antibiotics (vacidin A and its analogues) can be decreased by chemical modification. It has been shown that the ionic state of the polar head of the antibiotic molecule is essential for this activity. The effect of the net charge of the antibiotic molecule on association constant, K, between polyene and membrane-located cholesterol; and the number, n, of antibiotic molecules per one erythrocyte critical for lysis induction was investigated. In addition, changes in the structure of the polyene-cholesterol complex were monitored by circular dichroism spectroscopy. Zwitterionic native antibiotics (vacidin A and gedamycin), the negatively charged N'-acetyl derivatives and the positively charged methyl esters were used in these studies. The results presented indicate that two different phenomena are responsible for the decrease in the haemolytic activity of the compounds studied: for N'-acetyl derivatives the decrease of activity is mainly a result of lower affinity of negatively charged molecules to the membranes; for methyl esters the drastic decrease of activity is mainly a result of the different structure of the antibiotic-cholesterol complex. The permeabilizing species formed from these complexes are characterized by very low efficiency of ion permeation.