Antifungal Macrocycle Antibiotic Amphotericin B-Its Present and Future. Multidisciplinary Perspective for the Use in the Medical Practice.

This review is devoted to a broad analysis of the results of studies of the effect of macrocyclic antifungal polyene antibiotic amphotericin B on cell membranes. A detailed study of polyenes has shown that some of them can have not only antifungal, but also antiviral and antitumor effects. Under conditions of global pandemic fungal pathology develops especially quickly and in this case leads to invasive aspergillosis, which contributes to the complication of coronavirus infection in the lungs and even secondary infection with invasive aspergillosis. The treatment of an invasive form of bronchopulmonary aspergillosis is directly related to the immunomodulatory and immunostimulating properties of the macrocyclic polyene drug amphotericin B. The article presents experimental data on the study of the biological activity and membrane properties of amphotericin B and the effect of its chemically modified derivatives, as well as liposomal forms of amphotericin B on viral, bacterial and fungal infections. The mechanism of action of amphotericin B and its analogues is based on their interaction with cellular and lipid membranes, followed by formation of ion channels of molecular size in the membranes. The importance of these studies is that polyenes are sensitive to membranes that contain sterols of a certain structure. The analysis showed that pathogenic fungal cells containing ergosterol were 10-100 times more sensitive to polyene antibiotics than host cell membranes containing cholesterol. The high sterol selectivity of the action of polyenes opens broad prospects for the use of polyene antifungal drugs in practical medicine and pharmacology in the treatment of invasive mycoses and the prevention of atherosclerosis. In this context, it should be noted that polyene antibiotics are the main tool in the study of the biochemical mechanism of changes in the permeability of cell membranes for energy-dependent substrates. Chemical and genetic engineering transformation of the structure of polyene antibiotic molecules opens prospects for the identification and creation of new biologically active forms of the antibiotic that have a high selectivity of action in the treatment of pathogenic infections.

[Antifungal macrocycle antibiotic amphotericin B - its present and future. Multidisciplinary perspective for the use in the medical practice]. / Antigribkovyi makrotsiklicheskii antibiotik amfoteritsin V ­ nastoiashchee i budushchee. Mnogoprofil'naia perspektiva ispol'zovaniia v prakticheskoi meditsine.

This review is devoted to a broad analysis of the results of studies of the effect of macrocyclic antifungal polyene antibiotic amphotericin B on cell membranes. A multi-prolonged study of polyenes showed that some of them can have not only antifungal, but also antiviral and antitumor action. Fungal pathology develops especially quickly and in this case leads to invasive aspergillosis, which contributes to the complication of coronavirus infection in the lungs and even secondary infection with invasive aspergillosis in the context of a global pandemic. The treatment of an invasive form of bronchopulmonary aspergillosis is directly related to the immunomodulatory and immunostimulating properties of the macrocyclic polyene drug amphotericin B. The article presents experimental data on the study of the biological activity and membrane properties of amphotericin B and the effect of its chemically modified derivatives, as well as liposomal forms of amphotericin B on viral, bacterial and fungal infections. The mechanism of action of amphotericin B and its analogues is based on their interaction with cellular and lipid membranes, by forming ion channels of molecular size in them. The importance of these studies is that polyenes are sensitive to membranes that contain sterols of a certain structure. The analysis showed that pathogenic fungal cells containing ergosterol were 10-100 times more sensitive to polyene antibiotics than host cell membranes containing cholesterol. The high sterol selectivity of the action of polyenes opens up broad prospects for the use of polyene antifungal drugs in practical medicine and pharmacology in the treatment of invasive mycoses and the prevention of atherosclerosis. In this connection, it should be noted that polyene antibiotics are the main tool in the study of the biochemical mechanism of changes in the permeability of cell membranes for energy-dependent substrates. Chemical and genetic engineering transformation of the structure of polyene antibiotic molecules opens up prospects for the identification and creation of new biologically active forms of the antibiotic that have a high selectivity of action in the treatment of pathogenic infections.

Effect of Chemically Transformed Macrocyclic Polyene Antibiotics on Tumor Cells.

Comparative analysis of the effects of chemically transformed polyene antibiotics pimaricin, nystatin, lucensomycin, amphotericin B, and levorin on biological objects in vivo and in vitro revealed the greatest biological activity of original amphotericin B and levorin with its derivatives. The study also examined the effects of alkyl derivatives of amphotericin B and levorin modified in certain parts of the lactone ring on the lipid and biological membranes. It is established that methylated levorin possesses larger biological activity than the original antibiotic. Examination of the effects of alkyl derivatives of levorin and amphotericin B on cell cultures C6 (rat glioma) and HeLa (human cervical carcinoma) in vitro revealed the antitumor action of methylated levorin and original amphotericin B.

[Mechanism of action of macrolide antibiotic filipin on cell and lipid membranes].

The review deals with investigation of the mechanism of action of macrolide pentaene antibiotic filipin on cell and bilayer lipid membranes (BLM). The sterol hypothesis of the filipin mechanism of action is confirmed experimentally. The hemolytic and geneticocytological action of filipin, its action on virus infection and prion protein-associated diseases are discussed. The data on the mechanism of filipin action on BLM are presented. Filipin single ionic channels with conductance of 15-20 pS that is 3-4 times higher than that of the amphotericin channels were detected on cholesterol-containing membranes in filipin low concentration (1 x 10(-8) M) aqueous salt solution. Combined ionic channels of filipin and amphotericin B with conductance of 25-30 pS, that is 1.5-2 time lower than that of the clean filipin channels and 5 times higher that of the clean amphotericin B channels were also detected. The selectivity of filipin channels is mainly cationic. The potential of the penetrating ion on 10-fold gradient is +18 mV. The practical aspects of filipin application in biology, medicine and pharmacology are indicated.

[Red blood cells hemolysis under combined action of ultrasonic waves and polyene antibiotics].

Ultrasonic and induced hemolysis of red blood cells in the presence of alkyl derivatives of amphotericin B and levorin modified by the amino and carboxy groups was investigated. Amphotericin B derivatives such as metamphocin, ethamphocin and carboamphocin and levorin derivatives such as levoridon, isolevoridon and carbolevoridon were shown to have their own hemolytic activity in isotonic medium at concentrations of 10(-5) - 10(-4) M in erythrocyte suspension. The exposure of erythromycytes to pure dimethylsulfoxide (0.1-30%), the main solvent of polyene antibiotics, as well as to propamphocin and butamphocin did not induce hemolysis and had a stabilizing action an red blood cells during the ultrasonic hemolysis. It was suggested that changing of the mechanical strength of erythrocytes under the action of the polyenes was likely associated with impairment of microviscosity of the protein-lipid system of the erythrocyte membranes due to formation of structural ionic channels of molecular size.

[An aromatic heptaene antibiotic levorin and its derivatives in muscle activity]. / Geptaenovyi aromaticheskii antibiotik levorin i ego proizvodnye pri myshechnoi deiatel'nosti.

The review is concerned with the outlooks for the use of levorin, a membrane active and channel forming polyene antibiotic, and its alkyl derivatives in muscle activity. In complex with cholesterol and ergosterol, the aromatic heptaene antibiotic levorin forms structural ionic channels of the molecular size in the lipid and cell membranes. Levorin increases the membrane permeability for monosucrose and other neutral molecules as follows: H2O > urea > acetamide > glycerine > ribose > arabinose > glucose > saccharose. As a channel forming compound, levorin is able to induce in the cell membranes of the muscle fibres formation of additional channels permeable for the cations and to increase the flow of the energy dependent substrates to the cells and the outburst of the metabolites from them during intensive muscle activity. Levorin several times decreases the surface tension of aqueous solutions. In some models of experimental animals levorin promoted an increase of the blood fluidity and accelerated the blood stream in the blood vessels both in rest and in muscle activity. Physical load in a high power zone increases the intensity of lipid peroxidation that results in fatigue and lower physical efficiency. Possible prevention of an increase of the rate of free radical reactions by levorin and its alkyl derivatives providing higher antioxidant protection is discussed.

[Mechanism of the interaction of the individual components of levorin and nystatin preparations with lipid membranes]. / Issledovanie mekhanizma vzaimodeistviia individual'nykh komponentov preparatov levorina i nistatina s lipidnymi membranami.

Mechanism of interaction between separate levorin and nystatin component and lipid membranes was studied. It was shown that components A0, A1, A2 and A3 of levorin and components A1, A2, A3 and B1 of nystatin had a markedly pronounced membranotropic activity. Ion channel assembly and membrane conductivity were irreversibly controlled by concentration and membrane potential. Changes in selectivity of biomolecular lipid membranes depended on the structure of the antibiotics. The action of the levorin and nystatin components was based on increasing membrane conductivity by the mechanism of ion channel formation with parameters altering in relation to the antibiotic structure. Recommendations for directed synthesis of the antibiotic derivatives with high therapeutic efficacy are presented.

[Effect of amphotericin B added to one side of a membrane]. / Effekt amfoteritsina B, vvodimogo s odnoi storony membrany.

Amphotericin B which was added to the one side of a membrane in aqueous solutions with low pH 3.0 sharply increases the membrane conductance by the mechanism of channel forming. Long living ionic channels (20 sec) with large conductance dispersion (2-20 Ps) were found at the concentration 2 X 10(-8) M. Amphotericin B concentration which is necessary for obtaining single channels does not depend on cholesterol concentration in the membrane-forming solution in the range from 2 to 10 mg/ml. The effect of amphotericin B on the membrane depends on the phospholipid concentration in the membrane. The one-side selective permeability is the same as one under the symmetric action of the antibiotic. It is assumed that amphotericin B induced the membrane conductance by the mechanism of half-pores formation.

[Action of the alkyl derivatives of amphotericin B on the conductivity of bilayer lipid membranes]. / Deistvie alkil'nykh proizvodnykh amfoteritsina B na provodimost' bisloinykh lipidnykh membran.

Amphotericin B alkyl derivatives increased conductivity of bilayer membranes by formation of channels in them. The properties of such channels were studied. A new method for determination of the polyene antibiotic toxicity is described. The method is based on measurement of the constant of the relaxation time on the antibiotic removal from the membrane solution. It was shown that the amphotericin B alkyl derivatives had very low toxicity for the mammalian cells and were highly toxic for the fungal cells. These antibiotics may be used as new effective antifungal compounds.

[Relationship between ion channel properties and the structure of the lactone ring of polyene antibiotic molecules]. / Zavisimost' svoistv ionnykh kanalov ot struktury laktonnogo kol'tsa molekul polienovykh antibiotikov.

Properties of ionic channels created by amphoterecin B, nystatine and mycoheptin in phospholipid--cholesterol bilayer have been compared. Ionic conductivity and selectivity of channels as well as the frequency of transitions between an open state and a closed one depend on lacton ring structure. Appearance of one more carbonyl group in mycoheptin molecule leads to a decrease of channel anion permeability. Any pair of these antibiotics being added into different aqueous solutions create combined channels. These data confirm hypothesis that polyene antibiotics create channels of two half-pores formed in different monolayers of the membrane.

[Effect of ultraviolet light on sterol-containing membranes in nystatin solutions]. / Deistvie ul'trafioletovogo sveta na membrany, soderzhashchie steriny, v rastovorakh nistatina

The nystatin induced conductivity of artificial phospholipid membranes containing ergosterol or 7-dehydrocholesterol drops sharply under the action of ultra-violet light as a result of the transformation of these provitamins into adequate D2 and D3 vitamins. The UV-light does not change the conductivity of the membranes containing cholestrol in nystatin solution. Nystatin slightly effects the membrane resistance in the presence of D2 and D3 vitamins.