Identification of the structural elements of amphotericin B and other polyene macrolide antibiotics of the hepteane group influencing the ionic selectivity of the permeability pathways formed in the red cell membrane.
The selectivity of the transmembrane permeability induced by polyene antibiotics was studied in human erythrocytes and related to the hemolytic potency of the drugs. The selectivity induced was differently, dependent on the antibiotic structure in aromatic (vacidin A, gedamycin) and nonaromatic heptaenes (amphotericin B, candidin). Aromatic heptaenes were more effective than nonaromatic in inducing permeability to K+. For both groups of antibiotics, permeability to K+ was not affected by substitution at the carboxyl group but important differences in the induction of permeability to H+, OH- and Cl- were found. The strongly hemolytic aromatic heptaenes vacidin A and gedamycin exhibited much higher protonophoric activity than the nonaromatic ones: amphotericin B, and candidin. The protonophoric properties of aromatic heptaenes were related to the presence of a free carboxyl group in the antibiotic molecule. Indeed the esterification or amidation of the carboxyl group of vacidin A or gedamycin eliminated the ability of the antibiotic to increase H+ conductance and consequently diminished their hemolytic activity to an important extent. Both groups of antibiotics differed also in the efficiency of anion permeability induction. Only unsubstituted aromatic heptaenes, at high concentration, induced Cl-/OH- exchange and conductive flux of Cl- in a concentration-dependent manner. Substitution at the carboxyl group of vacidin A or gedamycin eliminated this property. Amphotericin B as well as its carboxyl-substituted derivatives formed a pathway characterized by low K+ over Cl- selectivity, whatever the concentration. The hemolytic activity, related to K+ permeability increased by heptaenes was dependent on simultaneous increase of the permeability to anions, and net KCl influx. Carboxyl-substituted derivatives of aromatic heptaenes presenting a remarkably high selectivity for K+, had consequently a very poor hemolytic activity.
Cybulska
B
B
Department of Pharmaceutical Technology and Biochemistry, Technical University of Gdansk, Poland.
Bolard
J
J
Seksek
O
O
Czerwinski
A
A
Borowski
E
E
D000666:Amphotericin B / Q000737:chemistry* / Q000494:pharmacology; D000838:Anions; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D002174:Candicidin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects; D002712:Chlorides / Q000032:analysis; D004910:Erythrocyte Membrane / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials; D010539:Permeability; D011090:Polyenes; D011188:Potassium / Q000032:analysis; D011522:Protons; D013329:Structure-Activity Relationship; D014634:Valinomycin / Q000737:chemistry / Q000494:pharmacology
D000838:Anions; D000900:Anti-Bacterial Agents; D002712:Chlorides; D011090:Polyenes; D011522:Protons; D002174:Candicidin; D014634:Valinomycin; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; C031985:vacidin A; D000666:Amphotericin B; D011188:Potassium