Interactions Of Macrolide Antibiotics (Erythromycin A, Roxithromycin, Erythromycylamine [Dirithromycin], And Azithromycin) With Phospholipids: Computer-Aided Conformational Analysis And Studies On Acellular And Cell Culture Models
Montenez, Jp.; Van Bambeke, F.; Piret, J.et al.
1999 • In Toxicology and Applied Pharmacology, 156 (2), p. 129-140
[en] The potential of 14/15 membered macrolides to cause phospholipidosis has been
prospectively assessed, and structure-effects examined, using combined
experimental and conformational approaches. Biochemical studies demonstrated drug
binding to phosphatidylinositol-containing liposomes and inhibition of the
activity of lysosomal phospholipase A1 toward phosphatidylcholine included in the
bilayer, in close correlation with the number of cationic groups carried by the
drugs (erythromycin A </= roxithromycin < erythromycylamine </= azithromycin). In
cultured cells (fibroblasts), phospholipidosis (affecting all major phospholipids
except sphingomyelin) was observed after 3 days with the following ranking:
erythromycin A </= roxithromycin < erythromycylamine < azithromycin
(roxithromycin could, however, not be studied in detail due to intrinsic
toxicity). The difference between erythromycylamine and azithromycin was
accounted for by the lower cellular accumulation of erythromycylamine. In
parallel, based on a methodology developed and validated to study drug-membrane
interactions, the conformational analyses revealed that erythromycin A,
roxithromycin, erythromycylamine, and azithromycin penetrate into the hydrophobic
domain of a phosphatidylinositol monolayer through their desosamine and cladinose
moieties, whereas their macrocycle is found close to the interface. This position
allows the aminogroups carried by the macrocycle of the diaminated macrolides
(erythromycylamine and azithromycin) to come into close contact with the
negatively charged phosphogroup of phosphatidylinositol, whereas the amine
located on the C-3 of the desosamine, common to all four drugs, is located at a
greater distance from this phosphogroup. Our study suggests that all macrolides
have the potential to cause phospholipidosis but that this effect is modulated by
toxicodynamic and toxicokinetic parameters related to the drug structure and
mainly to their cationic character.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Montenez, Jp.
Van Bambeke, F.
Piret, J.
Brasseur, Robert ; Université de Liège - ULiège > Gembloux Agro-Bio Tech
Tulkens, Pm.
Mingeot-Leclercq, Marie-Paule
Language :
English
Title :
Interactions Of Macrolide Antibiotics (Erythromycin A, Roxithromycin, Erythromycylamine [Dirithromycin], And Azithromycin) With Phospholipids: Computer-Aided Conformational Analysis And Studies On Acellular And Cell Culture Models
Agouridas C., Bonnefoy A., Chantot J. F. Antibacterial activity of RU64004 (HMR 3004), a novel ketolide derivative active against respiratory pathogens. Antimicrob. Agents Chemother. 41:1997;2149-2158.
Aubert-Tulkens G., Van Hoof F., Tulkens P. Gentamicin-induced lysosomal phospholipidosis in cultured rat fibroblasts. Lab. Invest. 40:1979;481-491.
Bartlett G. R. Phosphorus assay in column chromatography. J. Biol. Chem. 234:1959;466-468.
Brasseur R. TAMMO: Theoretical analysis of membrane molecular organization. Molecular Description of Biological Membrane Components by Computer-Aided Conformational Analysis. 1990;CRC Press, Boca Raton. p. 203-219.
Brasseur R., Deleers M., Malaisse W. J., Ruysschaert J. M. Conformational analysis of the calcium-A23187 complex at a lipid-water interface. Proc. Natl Acad. Sci. USA. 79:1982;2895-2897.
Brasseur R., Deleers M., Ruysschaert J. M. Mode of organization of amphiphilic molecules at lipid-water interface: A conformational analysis. J. Colloid. Interface Sci. 114:1986;277-281.
Brasseur R., Goormaghtigh E., Ruysschaert J. M. Theoretical conformational analysis of phospholipid bilayers. Biochem. Biophys. Res. Commun. 103:1981;301-310.
Brasseur R., Laurent G., Ruysschaert J. M., Tulkens P. M. Interactions of aminoglycoside antibiotics with negatively charged lipid layers: Biochemical and conformational studies. Biochem. Pharmacol. 33:1984;629-637.
Brasseur R., Vandenbranden M., Cornet B., Burny A., Ruysschaert J. M. Orientation into the lipid bilayer of an asymmetric amphipathic helical peptide located at theN. Biochim. Biophys. Acta. 1029:1990;267-273.
Bright G. M., Nagel A. A., Bordner J., Desa K. A., Dibrino J. N., Nowakowska J., Sciavolino F. C. Synthesis,in vitroin vivo. J. Antibiot. 41:1988;1029-1047.
Carlier M. B., Garcia-Luque I., Montenez J-P., Tulkens P. M., Piret J. Accumulation, release and subcellular localization of azithromycin in phagocytic and non-phagocytic cells in culture. Int. J. Tissue React. 16:1994;211-220.
Carlier M. B., Zenebergh A., Tulkens P. M. Cellular uptake and subcellular distribution of roxithromycin and erythromycin in phagocytic cells. J. Antimicrob. Chemother. 20(B):1987;47-56.
Chantot J.-F., Bryskier A., Gasc J.-C. Antibacterial activity of roxithromycin: A laboratory evaluation. J. Antibiot. 39:1986;660-668.
Chung L., Kaloyanides G., McDaniel R., McLaughin A., McLaughin S. Interaction of gentamicin and spermine with bilayer membranes containing negatively-charged phospholipids. Biochemistry. 24:1985;442-452.
Counter F. T., Ensminger P. W., Preston D. A., Wu C. Y., Greene J. M., Felty-Duckworth A. M., Kirst H. A. Synthesis and antimicrobial evaluation of dirithromycin (AS-E-136; LY237216), a new macrolide antibiotic derived from erythromycin. Antimicrob. Agents Chemother. 35:1991;1116-1126.
de Duve C., de Barsy T., Poole B., Trouet A., Tulkens P., Van Hoof F. Lysosomotropic agents. Biochem. Pharmacol. 23:1974;2495-2531.
Djokic S., Kobrehel G., Lopotar N., Kamenar B., Nagl A., Mrvos D. Erythromycin series. Part 13. Synthesis and structure elucidation of 10-dihydro-10-deoxo-11-methyl-11-azerythromycin A. J. Chem. Res. 1988.
Foulds G., Shepard R. M., Johnson R. B. The pharmacokinetics of azithromycin in human serum and tissues. J. Antimicrob. Chemother. 25(A):1990;73-82.
Grove D. C., Randall W. A. Assay Methods of Antibiotics. 1955;Medical Encyclopedia, New York.
Harris D. R., Mc Geachin S. G., Mills H. H. The structure and stereochemistry of erythromycin A. Tetrahedron Lett. 11:1965;679-685.
Kirst H. A., Creemer L. C., Paschal J. W., Preston D. A., Alborn W. E., Counter F. T., Greene J. M. Antimicrobial characterization and interrelationships of dirithromycin and epidirithromycin. Antimicrob. Agents Chemother. 39:1995;1436-1441.
Kirst H. A., Wind J. A., Leeds J. P., Willard K. E., Debono M., Bonjouklian R., Counter F. T. Synthesis and structure-activity relationships of new 9-NS. J. Med. Chem. 33:1990;3086-3094.
Kodavanti U. P., Mehendale H. M. Cationic amphiphilic drugs and phospholipid storage disorder. Pharmacol. Rev. 42:1990;327-354.
Kotretsou S., Mingeot-Leclercq M.-P., Constantinou-Kokotou V., Brasseur R., Georgiadis M. P., Tulkens P. M. Synthesis and antimicrobial and toxicological studies of amino acid and peptide derivatives of kanamycin A and netilmicin. J. Med. Chem. 38:1995;4710-4719.
Krämer S. D., Wunderli-Allenspach H. The pH-dependence in the partitioning behaviour of (RS)-[3. Pharm. Res. 13:1996;1851-1855.
Laurent G., Carlier M. B., Rollman B., Van Hoof F., Tulkens P. Mechanism of aminoglycoside-induced lysosomal phospholipidosis:In vitroin vivo. Biochem. Pharmacol. 31:1982;3861-3870.
Lowry O. H., Rosebrough N. J., Farr A. L., Randall R. J. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193:1951;265-275.
Luger P., Maier R. Molecular structure of 9-deoxy-11-deoxy-9-11-(imino(2-(2-methoxyethoxy)ethylidene)oxy)-(9S. J. Cryst. Mol. Struct. 9:1979;329-338.
Luke D. R., Foulds G. Disposition of oral azithromycin in humans. Clin. Pharmacol. Ther. 61:1997;641-648.
Massey E. H., Kitchell B., Martin L. D., Gerzon K., Murphy H. W. Erythromycylamine. Tetrahedron Lett. 2:1970;157-160.
Mingeot-Leclercq M. P., Laurent G., Tulkens P. M. Biochemical mechanism of aminoglycoside-induced inhibition of phosphatidylcholine hydrolysis by lysosomal phospholipases. Biochem. Pharmacol. 37:1988;591-599.
Mingeot-Leclercq M. P., Schanck A., Ronveaux-Dupal M. F., Deleers M., Brasseur R., Ruysschaert J. M., Tulkens P. M. Ultrastructural, physico-chemical and conformational study of the interactions of gentamicin andbis. Biochem. Pharmacol. 38:1989;729-741.
Mingeot-Leclercq M. P., Van Schepdael A., Brasseur R., Busson R., Vanderhaeghe H. J., Claes P. J., Tulkens P. M. New derivatives of Kanamycin B obtained by modifications and substitutions in position 6". II.In vitro. J. Med. Chem. 34:1991;1476-1482.
Montenez J. P., Van Bambeke F., Piret J., Schanck A., Tulkens P. M., Brasseur R., Mingeot-Leclercq M. P. Interaction of the macrolide azithromycin with phospholipids. II. Biophysical and computer-aided conformational studies. Eur. J. Pharmacol. 314:1996;215-227.
Puri S. K., Lassman H. B. Roxithromycin: A pharmacokinetic review of a macrolide. J. Antimicrob. Chemother. 20(B):1987;89.
Sheldrick G. M., Kojic-Prodic B., Banic Z., Kobrehel G., Kujundzic N. Structure of 9-deoxo-9a-NN. Acta Crystallogr., Sect. B. B51:1995;358-366.
Tulkens P. M. Intracellular distribution and activity of antibiotics. Eur. J. Clin. Microbiol. Infect. Dis. 10:1991;100-106.
Tulkens P. M., Beaufay H., Trouet A. Analytical fractionation of homogenates from cultured rat embryo fibroblasts. J. Cell Biol. 63:1974;383-401.
Tulkens P. M., Trouet A. The uptake and intracellular accumulation of aminoglycoside antibiotics in lysosomes of cultured rat fibroblasts. Biochem. Pharmacol. 27:1978;415-424.
Van Bambeke F., Gerbaux C., Michot J.-M., Bouvier d'Yvoire M., Montenez J. P., Tulkens P. M. Lysosomal alterations induced in cultured rat fibroblasts by long-term exposure to low concentrations of azithromycin. J. Antimicrob. Chemother. 42:1998;761-767.
Van Bambeke F., Montenez J. P., Piret J., Tulkens P. M., Courtoy P. J., Mingeot-Leclercq M. P. Interaction of the macrolide azithromycin with phospholipids. I. Inhibition of lysosomal phospholipase A1. Eur. J. Pharmacol. 314:1996;203-214.
Vassault A. Lactate dehydrogenase. Bergmeyer H. U. Methods of Enzymatic Analysis, Volume III/Enzyme I Oxydoreductases, Transferases. 1987;118-126 VHC Publishers, Weinheim.
Wiley P., Gerzon K., Flynn E. H., Sigal M. V. Jr., Weaver O., Quarck U. C., Monahan R. Erythromycin. X. Structure of erythromycin. J. Am. Chem. Soc. 79:1957;6062-6069.
