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8Органический синтез и биотехнология
УДК 557.123:547.241].012.1
V.V. Belakhov1, A.V. Garabadzhiu2 and V.A. Kolodyaznaya3
SEARCH FOR NEW DERIVATIVES OF POLYENE MACROLIDE ANTIBIOTICS AS POTENTIAL ANTIFUNGAL AGENTS FOR THE DELAYING OF DRUG RESISTANCE AND TREATMENT OF INVASIVE MYCOSES (review)
Schulich Faculty of Chemistry, Technion - Israel Institute of Technology, Haifa, Israel
St. Petersburg State Institute of Technology (Technical University), Moskovsky Pr., 26, St. Petersburg, 190013, Russia St. Petersburg State Chemical Pharmaceutical Academy, Professora Popova st., 14, St. Petersburg, 197022, Russia e-mail: chvalery@techunix.technion.ac.il
The results of authors' investigations, concerning the preparation of a series of semisynthetic derivatives of polyene macrolide antibiotics by chemical modification and modern nanotechnology methods, were summarized. It was shown that chemical modification, and especially phosphorylation, resulted in the formation of highly effective low-toxicity derivatives of polyene macrolide antibiotics with extended spectrum of biological action. The topical issues related to the drug resistance of fungal pathogens and increasing incidence of invasive mycoses and opportunistic fungal infections were considered.
Keywords: polyene macrolide antibiotics, chemical modification, nanotechnology, drug resistance, invasive mycoses, AIDS.
В.В. Белахов, А.В. Гарабаджиу, В.А. Колодязная
ПОИСК НОВЫХ
ПРОИЗВОДНЫХ
ПОЛИЕНОВЫХ
МАКРОЛИДНЫХ
АНТИБИОТИКОВ
как потенциальных
ПРОТИВОГРИБКОВЫХ
ПРЕПАРАТОВ
ДЛЯ ПРЕОДОЛЕНИЯ
ЛЕКАРСТВЕННОЙ
устойчивости
И ЛЕЧЕНИЯ
ИНВАЗИВНЫХ МИКОЗОВ (обзор)
Технион - Израильский институт технологии, Технион Сити, Хайфа, 32000, Израиль;
Санкт-Петербурский государственный технологический институт (технический университет), Московский пр., 26, Санкт-Петербург, 190013. Россия; Санкт-Петербургская государственная химико-фармацевтическая академия, ул. Профессора Попова, 14, Санкт-Петербург, 197022, Россия e-mail: chvalery@techunix.technion.ac.il
В обзорной статье обобщены результаты исследований авторов, касающиеся получения целого ряда полусинтетических производных полиеновых макролидных антибиотиков с помощью химической модификации и современных методов нанотехнологии. Показано, что химическая модификация, и в частности фосфорилирование, приводит к получению малотоксичных высокоэффективных производных полиеновых макролидных антибиотиков с расширенным спектром биологического действия. Рассмотрены актуальные вопросы, связанные с резистентностью патогенных грибковых микрорганизмов, возрастающим распространением инвазивных микозов и оппортунистических грибковых инфекций.
Ключевые слова: полиеновые макролидные антибиотики, химическая модификация, нанотехнология, лекарственная устойчивость, инвазивные микозы, СПИД.
1 Belakhov Valery V., PhD (Chem.), leading research scientist, Schulich Faculty of Chemistry, Technion - Israel Institute of Technology, e-mail: ohvalery@ techunix.technion.ac.il
Белахов Валерий Владимирович, канд. хим. наук, вед. науч. сотр., хим. факультет, Технион-Израильский институт технологии, e-mail: chvalery@ techunix.technion.ac.il
2 Garabadzhiu Alexander V., Dr Sci. (Chem.), vice-rector for scientific research, professor, laboratory of molecular pharmacology, St-Petersburg State Institute of Technology (Technical University), e-mail: gar-54@mail.ru
Гарабаджиу Александр Васильевич, д-р хим. наук, профессор, проректор по научной работе СПбГТИ (ТУ), e-mail: gar-54@mail.ru
3 Kolodyaznaya Vera A., PhD (Biol.), head of department of biotechnology, associate professor, St-Petersburg State Chemical Pharmaceutical Academy, e-mail: veank@mail.ru
Колодязная Вера Анатольевна, канд. биол. наук, доцент, зав. каф. биотехнологии, СПГХФА, e-mail: veank@mail.ru
Дата поступления - 22 июня 2015 года Received June 22, 2015
DOI 10.15217/issn1998984-9.2015.30.
Introduction
Fungal infections represent one of the biggest problems in health care today. Factors responsible for growth of fungal diseases include continuing pollution of the environment, increased background radiation level, irrational use of broad-spectrum antibiotics, intensive use of cytotoxic drugs and immunosuppressants, etc. [1-3]. Among fungal diseases, invasive mycoses are becoming an increasingly urgent problem for practical medicine due to growing immunocompromised patient populations [4-6]. The current availability of approved systemic antifungal antibiotics is recognized inadequate [7-9], and the progress in development of new antifungals does not keep with the incidence rate of mycological diseases, particularly invasive fungal infections which constitute a real and a growing problem of modern medicine [10-12]. Hence, effective application of antifungal drugs, especially of polyene macrolide antibiotics (PMAs), in treatment of various forms of mycoses is an important aspect of fighting fungal infections.
Polyene macrolide antibiotics amphotericin B, levorin, nystatin, pimaricin, candicidin, and other find wide practical application in medicine for treating both superficial and deep mycoses [4-6]. This is a large group of natural compounds, including over 200 agents that are active against yeasts and yeast-like and filamentous fungi, both saprophytic and pathogenic [13-18]. However, the PMAs used in medical practice do not fully satisfy clinicians' needs because of a limited efficacy. This is due to poor solubility in water [4-6] and high toxicity (mainly nephrotoxicity) [7-9], as well as to the emergence of PMA resistance among fungal pathogens [19, 20]. Thus, the search for new PMA derivatives with improved medical and biological properties remains an important challenge.
Preparation of new semisynthetic PMA derivatives by chemical modification
Polyene macrolide antibiotics are a class of polyfunctional compounds characterized by the presence of a large lactone ring (26-33 atoms) containing a series (4-7) of conjugated double bonds [10-14]. Based on the number of double bonds, PMAs are subdivided into tetraenes, pentaenes, hexaenes, and heptaenes. The unsaturated side of the macrolide ring is rigid and hydrophobic, and the other, flexible (polyol) side renders the PMA molecule hydrophilic. Other important structural components of PMAs include a carboxyl group and an amino group within the carbohydrate moiety. Most of the PMAs investigated up to now contain an aminosugar mycosamine (3-amino-3,6-dideoxy-D-mannose). Accordingly, the vast majority of PMA derivatives were obtained by modification of these antifungals specifically at the carboxyl or amino group (Figure).
OH NH2
Figure.
Structure of heptaene macrolide antibiotic amphotericin B.
Various semisynthetic derivatives of PMAs, obtained by chemical modification, have been described in the literature so far [11, 12, 21-25], while information relating to the preparation of organophosphorus derivatives of these antifungal agents has been lacking. As known, organophosphorus compounds find extensive applications
in diverse industries and are produced commercially on ever-expanding scale [26-30]. A particularly valuable property possessed by organophosphorus compounds is their biological activity, making them suitable for medical applications [31-37]. Therefore, the use of organophosphorus chemistry-based synthetic methods for chemical modification of biologically active compounds, above all antibiotics, appears to be a promising approach to develop highly effective drugs. For chemical modification of PMAs we suggested a hydrophosphorylation method based on the use of hypophosphorous acid and aromatic aldehydes. This process can be regarded as a version of the Kabachnik-Fields reaction [26, 38, 39]. The first stage of the process consists in addition of the primary amino group in the carbohydrate moiety of the PMA molecule to the carbonyl group of the aromatic aldehyde to form an azomethine intermediate. In the second stage, hypophosphorous acid reacts at the C=N bond of the azomethine intermediate to form hydrophosphoryl PMA derivatives. This method has been successfully employed for synthesis of hydrophosphoryl derivatives of levorin [40], nystatin [41], amphotericin B [42], mycoheptin [43], pimaricin [44], and lucensomycin [45]. We showed that the chemical modification of pimaricin with the use of different dialkyl phosphites and 4-bromobenzaldehyde, also under the Kabachnik-Fields reaction conditions, resulted in the formation of 3'-N-a-[dialkoxy(diphenoxy)phosphinoyl] benzyl derivatives of this tetraene macrolide antibiotic [46]. Also, we explored the potential of the Atherton-Todd reaction for chemical modification of amphotericin B [47-49]. For example, the reaction with a variety of dialkyl(aryl)phosphites in the presence of an organic base yielded dialkyl(aryl) amidophosphonate derivatives of this heptaene macrolide antibiotic. The chemical modification of pimaricin with diethyl-(2-chloroethynyl)phosphonate proceeded with high selectivity to form the corresponding phosphorylated aldoketenimine derivative, i.e., the organophosphorus agent reacted with the primary amino group of mycosamine [50, 51].
Apart from organophosphorus derivatives, fluorinated derivatives of PMAs were prepared by reacting amphotericin B [52] and nystatin [53] with perfluorocarboxylic acid anhydrides. Organofluorine derivatives of levorin were synthesized by esterification of this heptaene macrolide antibiotic with organofluorine alcohols [54]. Reactions with trialkylchlorosilanes yielded N-trialkylsilyl derivatives of nystatin [55, 56]. The N-benzyl derivatives of amphotericin B [57] and pimaricin [58, 59] were prepared under the reductive amination conditions, and N-aryl-substituted derivatives of pimaricin, by a nucleophilic aromatic substitution reaction [60]. Biological tests of the semisynthetic PMA derivatives revealed pronounced antifungal activity toward a large group of pathogenic fungal microorganisms, above all yeast-like fungi of the genus Candida, as well as a 3-5-fold reduction in toxicity compared to the initial antibiotics. Furthermore, chemical modification allows introducing various functional groups, e.g., hydrophosphoryl groups, into PMAs, whereby the water solubility of the resulting levorin, nystatin, amphotericin B, mycoheptin, pimaricin, and lucensomycin derivatives [40-45, 61, 62] and, consequently, the biopharmaceutical properties of the antifungal agents can be significantly improved.
Chemical modification of biologically active compounds is known to produce, in certain cases, changes in the spectrum of biological activity and reduction in the toxicity of the resulting derivatives [21, 22, 31, 32]. Previously, antiviral [63, 64] and antitumor [65, 66] activities, nonspecific for polyene macrolide antibiotics, were revealed by various researchers. It was shown that the mechanism of action of these antifungal antibiotics involves reorientation of the lipid (sterol) component of the virion surface or virus-specific receptors of the cellular cytoplasmic membranes, which renders the virus inactive or prevents its penetration into sensitive cells [63, 64, 67]. Hence, studying the antiviral activity of the resulting PMA derivatives was of interest. We showed that chemical modifi-
cation caused changes in the spectrum of biological activity of PMAs. For example, additional virological tests revealed high antiviral activity of a number of semisynthetic derivatives of levorin [40], nystatin [41], amphotericin B [42], mycoheptin [43], and lucensomycin [45] that we prepared against DNA-containing variolovaccine virus and RNA-containing viruses, oncogenic Rous sarcoma virus and types A and B infectious influenza virus. Of particular interest are the findings obtained with the RNA-containing Rous sarcoma retrovirus model for the hydrophosphoryl derivatives of these PMAs, since this model was proposed as a suitable option for anti-acquired immunodeficiency syndrome (AIDS) drug screening and studying [63, 64].
Search for liposomal preparations and nanoparticles of PMAs
In recent years, approaches to reduce the toxicity and improve the pharmacokinetic properties of PMAs (mainly amphotericin B and nystatin) from biopharmaceutical perspective have become a frequent practice. Accordingly, various derivatives of amphotericin B, specifically liposomal formulations (AmBisome), lipid complexes (Abelcet), and colloidal dispersions (Amphocil) [68-73], as well as liposomal nystatin formulation (Nyotran) [74-77], were prepared. Liposomal amphotericin B (AmBisome) and nystatin (Nyotran) formulations are closed, spherical vesicles formed when some polar lipids, e.g., phospholipids and cholesterol, are dispersed in water. When homogenized in aqueous solutions, phospholipids arrange themselves into single or multiple concentric bilayer membranes [7880]. Due to the presence of lipophilic groups, amphotericin B can be incorporated into the lipid bilayer of liposomes. The drug distributes as intact liposomes to tissues where there may be sites of fungal infection. Active substance is released from liposomes only when contacting the fungal pathogen cells, so that normal tissues remain intact. Further advantages offered by liposomal PMA formulations include lower level of toxicity, prolonged pharmacokinetic properties, and better tolerance [68-73]. Abelcet is the amphotericin B lipid complex consisting of amphotericin B complexed with two lipids, dimyristoylphosphatidylcholine and dimyri stoylphosphatidylglycerol, in a 1:1 drug to lipid molar ratio. Though not extensively tested in the clinical setting, this formulation is now successfully applied for treatment of candidiasis, aspergillosis, cryptococcosis, and other severe fungal infections [7-9]. Amphocil, a colloidal suspension of amphotericin B, is comprised of equimolar amounts of this antibiotic and cholesterol sulfate [81-83]. It is effective in therapy of severe deep mycoses, particularly pulmonary aspergillosis. Like AmBisome, the Abelcet and Amphocil formulations exhibit significantly reduced nephrotoxicity compared to amphotericin B.
Liposomes are attractive to researchers due to nontoxicity, biodegradability, and ease of preparation [84-86]. Furthermore, an essential advantage offered by liposomes is their high variability. For example, by varying the technique of formation of lipid vesicles and incorporating various molecules therein it is possible to broadly vary the characteristics of liposomes as carriers of biologically active compounds. One of the problems with using liposomal carriers is the inherent physical and chemical instability of phospholipid's membranes, which is the cause of lipid bilayer destabilization and liposome degradation [87, 88]. The stability of liposomes and their circulation time in the bloodstream can be enhanced by modification with polymers, including polyethylene glycol and its synthetic derivatives, which prevent liposomes from early degradation [89, 90].
Since recently, a significant role in the search for innovative PMA derivatives has been assigned to nanotechnology approaches, because nanotechnology research in medicine is focused on preparation of a next generation of agents that offer higher efficiency of drug delivery and enhanced stability [91-96].
A number of studies have been published which employed nanosized structures, fullerenes and carbon nanotubes, as drug containers [97, 98]. Fullerenes exhibit unique properties resulting from their high reactivity which is due to abundant carbon dangling bonds; one way of their injection into the body is via encapsulation in lipid vesicles [99]. However, pure fullerenes are insoluble in aqueous media, which makes them hardly suitable for biomedical applications. In this regard it was shown [100] that adding functional groups makes fullerenes bioavailable and therefore more useful in biological systems. Carbon nanotubes have a high affinity for lipids and are capable of forming stable supramolecular complexes (assemblies) with peptides and nucleic acids [101, 102] and of encapsulating these molecules [103, 104]. Like in the case with fullerenes, the efficiency of application of nanotubes as containers was enhanced by functionalization. Polyelectrolyte and nanocomposite microcapsules proved to be an effective option for drug delivery [105]. They were obtained by the polyion assembly technique in which sequential adsorption of oppositely charged polyelectrolyte molecules on the colloidal particle surface was followed by the dissolution and removal of the initial template [106]. This technique allows preparing capsules of broadly varying sizes (from 50 nm to 50 |jm), whose shells can be selected from a wide range of materials including virtually any synthetic and natural polyelectrolytes [106, 107], lipid bilayers, inorganic nanoparticles (e.g., silver, gold, or iron(111) oxide nanoparticles), and polyvalent metal ions and which possess multifunctional walls with controllable thickness [108, 109]. The controlled permeability properties of the capsule wall to any low- and high-molecular-weight compounds were emphasized [110]. Specifically, inorganic nanoparticles of magnetite, Fe3O4, possessing pronounced magnetic properties are introduced into the microcapsule shell composition in the synthesis stage, so that the motion of the capsules under an external magnetic field can be controlled [105]. At the same time, there are only scarce published data on the use of nanoscale containers for targeted transport of drugs (except for liposomes), and issues of biological safety of nanomaterials remain poorly understood [92-94]. By now, data on the toxicity of fullerenes [111] and carbon nanotubes [112] as assessed in pharmacological studies using animal models have been reported. The key findings and recommendations on preparation of various nanoparticles, especially of drugs, that emerged from studies in [97-112], have been examined and further put into practical use by researchers for synthesis of nanoparticles of drugs, including PMAs. For example, publications released during the past two decades (1990-2009) and summarized in reviews [113-116] emphasized the promise of targeted screening of PMA nanoparticles for the preparation of PMA derivatives with pronounced antifungal activity. In recent years, various research teams successfully applied modern nanotechnology methods to produce a range of heptaene macrolide antibiotic amphotericin B nanoparticles [117124]. The resulting amphotericin B nano- particles displayed pronounced antifungal activity and favorably compared with the initial antibiotic in terms of toxicity and stability. Nystatin [125-127] and natamycin (pimaricin) [128, 129] nanoparticles also showed better bioavailability and lower toxicity compared to the initial antibiotic, prompting suggestions that these are promising antifungals for treatment of candidiases of different etiologies. We obtained nanoparticles of tetraene macrolide antibiotics pimaricin, nystatin A1, lucensomycin, and tetramycin B, coated with Tween 80 surfactant [130]. They were prepared in two steps: (1) synthesis of a D,L-lactide (LA)-polyethylene glycol (PEG) copolymer and (2) use of the resulting LA-PEG copolymer for the preparation of nanoparticles of the tetraene macrolide antibiotics with the aid of Tween-80 surfactant. Our studies showed that, through production of nanoparticles by the technique developed, the biopharmaceutical properties of these tetraene macrolide antibiotics were greatly improved.
Drug resistance in pathogenic fungi and its delaying through the use of new PMA derivatives
Systemic administration of antifungal agents, including PMAs, for treatment of mycoses has resulted in emergence of antifungal resistance in many of pathogenic fungi [131-134]. It is known that resistance among fungi can intrinsic or acquired. Intrinsic (primary) resistance refers to fungal species that lack a target for antimycotic and represents an extremely rare occurrence [135-138]. In practice, intrinsic resistance is defined as the ability of a particular fungal species to survive in the presence of clinically achievable concentrations of antimycotic. Acquired (secondary) resistance implies the ability of some fungal strains to survive in the presence of drug concentrations that are lethal to most members of the population of pathogenic fungal microorganisms [136, 138]. Secondary resistance is developed mostly through acquisition of new genetic information or alteration of gene expression [139-141]. Important parameters indicating the development of secondary resistance are increased minimum inhibitory concentration of the drug and structural alteration of the antimycotic target site as a result of spontaneous mutations in the genes encoding the drug targets, leading to a decrease in (or loss of) the binding capacity of the antimycotic drug to its target [142 -144].
Polyene macrolide antibiotics are known to exert both fungistatic and fungicidal effects due to ability for binding ergosterol in fungal cell membrane, resulting in the loss of membrane integrity, release of cytoplasmic contents, and eventual cell death [4-6, 13, 14]. Since PMAs are targeting structural elements of fungal cells rather than enzymes, the development of resistance may be the result of complex genetic processes leading to alterations in the biosynthesis of the membrane components [6-9, 145]. Because of a relatively low probability of such events, the frequency of PMA resistance among fungal pathogens is comparatively low. To date, the biochemical and genetic aspects of fungal resistance to PMAs are not adequately understood; some researchers support the hypothesis associating the resistance with a decrease in the level of ergosterol in the cytoplasmic membrane and increases in those of its structural analogs [146-150]. Experiments [147] showed that the new sterols detected in cells of resistant strains are often ergosterol intermediates. Also, they can be the products of the sterol component synthesis by bypass routes. Biochemical tests showed that, in resistant fungal strains, the transmethylation reaction of lanosterol is violated, and sterols are further synthesized by a different route which does not involve the transfer of methyl groups [146, 147]. Subsequent studies demonstrated that the PMA resistance in fungal microorganisms is due to shielding, or reorientation, of the membrane sites interacting with PMAs [151, 152]. These changes may be the result of mutations or phenotypic modifications affecting membrane components other that sterols. Phospholipids can be directly involved in the action produced by PMAs on fungal cells. As demonstrated in [146, 147, 153, 154], the damaging effect of PMAs may depend on the phase state of the membrane as determined by the presence of unsaturated bonds in the fatty acids of phospholipids.
As noted by several researchers [152, 153, 155], the PMA resistance in yeast and yeast-like fungi greatly varies with the medium composition and culture conditions. For example, the PMA resistance was shown to increase as the culture transits from the logarithmic to stationary growth phase. It was assumed that this kind of resistance is underlain by age-related structural alterations of the cell walls, resulting in reduced accessibility of specific sites on the fungal membrane for PMAs with which they interact.
In [153, 156, 157] it was shown that one possible mechanism of fungal resistance to PMAs can be active efflux of drugs out of the fungal cell.
Based on our previous findings about chemical transformation of PMAs, with due regard to the latest
publications concerning the PMA resistance mechanisms in fungal pathogens [19, 140, 142, 157], the semisynthetic PMA derivatives obtained were shown to be effective against many resistant strains of fungal pathogens, primarily yeast-like fungi of the genus Candida [45, 47, 49, 158-166].
A special emphasis and attention should be given to the search for new antimycotics, including semisynthetic PMA derivatives, displaying pronounced fungicidal activity specifically against resistant fungal pathogens. This is because the problem of their resistance to the antimycotics that are currently available in clinical arsenal has taken alarming proportions and become one of the major concerns in treating mycoses of various etiologies in both developed and developing countries. This issue was addressed by the World Health Organization (WHO) in its International Program "WHO Global Strategy for Containment of Antimicrobial Resistance" aimed to prevent steady increase in the number of microorganisms (including fungal pathogens) that display resistance associated both with long-term systemic use of antibiotics and administration of drugs that have been recently introduced into clinical practice [167].
Prospects for medicinal applications of new PMA derivatives in treatment of invasive mycoses
Wide dissemination of new medical technologies, diagnostic and therapeutic procedures, cytostatic and immunosuppressive therapy, transplantation, and HIV pandemic, as well as advances in the treatment of bacterial infections, have led to increasing population of immunocompromised patients at a high risk of invasive mycoses [7, 9, 168]. The latter are a group of infectious complications caused by invasion (penetration) of various tissues of the human body by fungi. Many researchers note that the incidence of invasive mycoses progressively increases, with the associated mortality rate remaining very high (40-90%) [169-171] and Candida spp., Aspergillus fumigatus, and Cryptococcus neoformans being the main causative agents of these diseases. The major implications of resistance include clinical ineffectiveness of many of antifungal drugs used for treatment of mycoses and changes occurring in the spectrum of fungal pathogens, in particular, the prevalence of non-albicans species of yeast-like fungi of the genus Candida, e.g., Candida glabrata and Candida krusei [1, 9, 172, 173]. Also, invasive mycoses are being observed at increasing frequencies when due to various strains of Fusarium spp., Scedosporium spp., Rhizopus spp., Mucor spp., etc., which are becoming ever more resistant to the most common antifungal agents. As pointed out by several researchers, the progress in development of new antifungals has significantly lagged behind that of antibacterial agents [79, 174-176]; the major limiting factors are tolerance toward systemic antifungals and development of resistance thereto in invasive fungal pathogens [177-179]. Fungi are eukaryotes whose cells, though having a cell wall, are structurally closer to the cells of mammals than to those of bacteria [180, 181]. Furthermore, fungal cells proliferate slower than do bacterial cells, so their quantitative analysis is typically difficult, particularly in filamentous fungi, which complicates the adequate and reproducible assessment of the efficacy of antifungal drugs, and especially of new antimycotics [3-6].
Another challenge facing clinical medicine concerns the so-called AIDS-related opportunistic fungal infections. AIDS is the final stage of HIV (human immunodeficiency virus) infection, a slowly progressive infectious disease which inflicts severe damage primarily to the immune system [182, 183]. HIV belongs to the family of RNA-containing retroviruses and is classified into the lentivirus subfamily, i.e., that of viruses causing slow infections. The human immunodeficiency virus displays selective tropism for T4 cells (T-helper-inducer lymphocytes) responsible for serious impairment of immune responses, resulting in high susceptibility to opportunistic infections and tumors in patients, which are the ultimate
cause of their death [184-186]. By now, cases of acquired immune deficiency syndrome have been commonly reported from most countries of the world. Furthermore, over the past 20 years there has been a steady increase in HIV morbidity and, to an even greater degree, in the rate of acquisition of HIV infection, which reached enormous levels. This allowed HIV to be regarded as a pandemic whose combating is a high-priority issue of global significance, as declared by the WHO [185, 187-190].
Long-term studies showed that opportunistic infections in patients with AIDS are due to protozoan, fungal, bacterial, or viral pathogens and constitute the leading cause of death of these patients [191]. Among fungal infections that cause opportunistic diseases special mention should be made of yeast-like fungi of the genus Candida. They may be responsible for clinical forms of both superficial and deep fungal infections (candidiasis), which is a common opportunistic infection in patients with HIV [135, 192, 193]. According to the latest reports, the genus Candida is comprised of about 200 species, among which only selected ones are pathogenic, with Candida albicans, Candida glabrata, Candida krusei, and Candida tropicalis being the four most common fungal pathogens in humans [194-197]. These yeast-like fungi can create a number of toxic substances and possess the following factors of aggression: endotoxins, enzymes (phospholipase, protease, collagenase), and cellular components [186]. The interaction of these fungi with cells appears in diversified forms, ranging from superficial candidiasis, when the host cell integrity is not lost (carriage state), to candidemia due to penetration of fungi into the bloodstream and formation of multiple lesions in internal organs.
Other species identified as the most important opportunistic fungi are (1) Cryptococcus neoformans, which causes cryptococcosis affecting lungs, bone marrow, lymph nodes, liver, joints, etc. and (2) Aspergillus fumigatus responsible for development of pulmonary aspergillosis, as well as aspergillosis of brain, thyroid gland, spleen, and kidneys [182, 183, 185, 186]. Also reported were cases of other opportunistic fungal infections in patients with AIDS, e.g., histoplasmosis, blastomycosis, zygomycosis, and paracoccidioidomycosis [198-204].
In this context, the use of PMAs having a broad antifungal spectrum of action is essential for the prevention and treatment of invasive mycoses and opportunistic fungal infections in patients with AIDS. However, the therapeutic efficacy of the PMAs that have enjoyed mycological applications so far is limited due to a variety of reasons, as mentioned above. Our studies revealed a pronounced antifungal activity expressed by the semisynthetic amphotericin B derivatives obtained by us against a number of resistant strains of pathogenic fungal microorganisms, e.g., Candida albicans, Aspergillus fumigatum, and Cryptococcus neoformans, that cause opportunistic fungal infections [46, 47, 49, 166, 205-209].
Conclusion
Chemical modification of PMAs yielded a variety of semisynthetic derivatives with improved pharmacological and biopharmaceutical properties, which display pronounced activity against various fungal infections, including invasive and opportunistic mycoses, and have an extended spectrum of biological action. Great opportunities for mycological applications are offered by the innovative PMA derivatives obtained by nanotechnology methods. Analysis of the causes of resistance in fungal pathogens suggests that studying the structure and functions of cell membranes of these PMA-resistant microorganisms is of critical importance for finding ways to delay drug resistance in fungal pathogens, as well as for gaining a deeper insight into the action mechanism of these antifungal antibiotics. Comprehensive in vivo medical and biological tests will allow evaluating the prospects for the application of the semisynthetic PMA derivatives obtained as potential antimycotics for drug therapy of mycoses.
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