Azoles Dotaz Zobrazit nápovědu
Candida albicans has several virulence factors at its disposal, including yeast-hyphal transition associated with biofilm formation, phospholipases, proteases and hemolytic activity, all of which contribute to its pathogenesis. We used synthetic derivative LL-III/43 of antimicrobial peptide lasioglossin LL-III to enhance effect of azoles on attenuation of C. albicans virulence factors. LL-III/43 was able to inhibit initial adhesion or biofilm formation of C. albicans strains at 50 µM. Azoles, however, were ineffective at this concentration. Using fluorescently labeled LL-III/43, we observed that peptide covered C. albicans cells, partially penetrated through their membranes and then accumulated inside cells. LL-III/43 (25 µM) in combination with clotrimazole prevented biofilm formation already at 3.1 µM clotrimazole. Neither LL-III/43 nor azoles were able to significantly inhibit phospholipases, proteases, or hemolytic activity of C. albicans. LL-III/43 (25 µM) and clotrimazole (50 µM) in combination decreased production of these virulence factors, and it completely attenuated its hemolytic activity. Scanning electron microscopy showed that LL-III/43 (50 µM) prevented C. albicans biofilm formation on Ti-6Al-4 V alloy used in orthopedic surgeries and combination of LL-III/43 (25 µM) with clotrimazole (3.1 µM) prevented biofilm formation on urinary catheters. Therefore, mixture of LL-III/43 and clotrimazole is suitable candidate for future pharmaceutical research.
- MeSH
- antifungální látky farmakologie MeSH
- azoly farmakologie MeSH
- biofilmy účinky léků růst a vývoj MeSH
- Candida albicans účinky léků MeSH
- erytrocyty účinky léků MeSH
- faktory virulence MeSH
- fosfolipasy antagonisté a inhibitory MeSH
- hemolýza účinky léků MeSH
- hydrofobní a hydrofilní interakce účinky léků MeSH
- kationické antimikrobiální peptidy chemická syntéza farmakokinetika MeSH
- lidé MeSH
- proteasy metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Pichia fabianii, a yeast rarely causing human infections, was isolated from the blood of a patient with aortic valve endocarditis. The isolates were initially identified biochemically as Candida pelliculosa, but based on direct sequencing of the ITS2 region of rRNA, they were subsequently reidentified as P. fabianii. Antifungal therapy with fluconazole and later with voriconazole led to the development of resistant variants which had high MIC values to both antifungals. Strong biofilm formation by this yeast could also have played a role in the development of its resistance and allowed for its persistence on the infected valve during antifungal therapy. To our knowledge, this is the first published case of endocarditis and the fourth human infection caused by this yeast species.
- MeSH
- antifungální látky farmakologie MeSH
- azoly farmakologie MeSH
- biofilmy MeSH
- dospělí MeSH
- endokarditida farmakoterapie mikrobiologie MeSH
- financování organizované MeSH
- fungální léková rezistence MeSH
- lidé MeSH
- mykózy farmakoterapie mikrobiologie MeSH
- Pichia fyziologie izolace a purifikace patogenita účinky léků MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
With emerging fungal infections and developing resistance, there is a need for understanding the mechanisms of resistance as well as its clinical impact while planning the treatment strategies. Several approaches could be taken to overcome the problems arising from the management of fungal diseases. Besides the discovery of novel effective agents, one realistic alternative is to enhance the activity of existing agents. This strategy could be achieved by combining existing antifungal agents with other bioactive substances with known activity profiles (combination therapy). Azole antifungals are the most frequently used class of substances used to treat fungal infections. Fluconazole is often the first choice for antifungal treatment. The aim of this work was to study potential synergy between azoles and 1,4-dihydropyridine-2,3,5-tricarboxylate (termed derivative H) in order to control fungal infections. This article points out the synergy between azoles and newly synthesized derivative H in order to fight fungal infections. Experiments confirmed the role of derivative H as substrate/inhibitor of fungal transporter Cdr1p relating to increased sensitivity to fluconazole. These findings, plus decreased expression of ERG11, are responsible for the synergistic effect.
- MeSH
- ABC transportéry antagonisté a inhibitory genetika MeSH
- antifungální látky chemická syntéza farmakologie terapeutické užití MeSH
- Candida albicans účinky léků genetika MeSH
- dihydropyridiny chemická syntéza farmakologie terapeutické užití MeSH
- flukonazol farmakologie terapeutické užití MeSH
- fungální léková rezistence účinky léků MeSH
- fungální proteiny antagonisté a inhibitory genetika MeSH
- kandidóza farmakoterapie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- mutace MeSH
- regulace genové exprese u hub účinky léků MeSH
- sterol-14-demethylasa genetika MeSH
- synergismus léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- financování organizované MeSH
- Publikační typ
- abstrakty MeSH
Tato přehledná práce pojednává o nových antifungálních léčivech. Úměrně rostoucímu výskytuzávažných infekcí vyvolaných kvasinkami a nižšími houbami především u imunokomprimovanýchči jinak citlivých osob stoupá potřeba hledání nových antifungálních léčiv. Stručně je nastíněnsoučasný stav farmakoterapie, největší pozornost je věnována nově vyvíjeným látkám. V současnostipoužívané látky mnohdy nesplňují požadavky moderní antifungální terapie, např. skupina azolů jepouze fungistaticky účinná a často u nich vzniká rezistence, v případě polyenových antimykotik jelimitujícím faktorem jejich toxicita.V klinickém vývoji jsou léčiva typumodifikovaných azolů a nováskupina echinokandinů a pneumokandinů. Další slibná léčiva v preklinickémvývoji zahrnují různésloučeniny, které u hub inhibují syntézu peptidů, lipidů a buněčné stěny.
The present review paper deals with novel antifungal drugs. The lack of new antifungal drugsascends proportionally to the increasing occurrence of serious infections caused by yeast and fungimainly at immunocompromised or in other way sensitive patients. The topical state of pharmacotherapyis briefly drawn out; most attention is given to newly developed active entities. Establishedagents do not satisfy the medical need completely, azoles are fungistatic and vulnerable to resistance,whereas polyenes cause serious host toxicity. Drugs in clinical development include modified azolesand a new class of echinocandins and pneumocandins. Other promising novel agents in preclinicaldevelopment include several inhibitors of fungal protein, lipid and cell wall syntheses.
Azoles antifungals are widespread used drugs for various medicinal indications. These drugs are well known for their numerous drug-drug interactions, which are believed to occur via inhibition of CYP3A4 enzymatic activity and consequently altering pharmacokinetic of co-administered drugs. In the current communication a complex view on the molecular interactions between azoles antimycotics and CYP3A4 is presented. Beside inhibition of CYP3A4 catalytic activity, azoles influence transcriptional activity of pregnane X receptor (PXR) and consequently expression of drug-metabolizing enzymes, including CYP3A4. Interactions between azoles and PXR occur by multiple mechanisms, including modulation of ligand-dependent activation of PXR (agonism, antagonism) or affecting recruitment of PXR co-activators SRC-1 (steroid receptor co-activator 1) and HNF4α (hepatocyte nuclear factor 4α). Miconazole and ketoconazole are antagonists of glucocorticoid receptor (GR), therefore these drugs inhibit GR-mediated expression of PXR and drug metabolizing cytochromes P450. In addition, PXR and GR are key regulators of intermediary metabolism (e.g. carbohydrate, lipids or bile acids homeostasis) and many other cellular functions (e.g. immune response), hence, the interactions between azoles and PXR/GR are of broader physiological importance. In conclusion, while inhibition of CYP3A4 enzymatic activity by azoles is considered as primary cause of azoles drug-drug interactions, the effects of azoles on PXR and GR should be taken in account. Apart from CYP3A4, azoles influence the expression and activity of others drug-metabolizing cytochromes P450.
- MeSH
- aktivace enzymů MeSH
- antifungální látky farmakologie MeSH
- azoly farmakologie MeSH
- cytochrom P-450 CYP3A metabolismus MeSH
- inhibitory cytochromu P450 CYP3A MeSH
- lékové interakce MeSH
- lidé MeSH
- receptory glukokortikoidů metabolismus MeSH
- steroidní receptory metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Paleta antimykotik používaných k léčbě systémových mykóz je chudá. Nejstarším a dosud uznávaným „zlatým standardem“ je polyen amfotericin B (AmB), který má nejširší spektrum účinku, vykazuje nejméně rezistencí, avšak léčbu mohou provázet toxické projevy, zejména riziko nefrotoxicity. „Lipidové“ formy AmB (Abelcet, Amphocil, AmBisome) s pouze 20% rizikem nefrotoxicity tento problém částečně řeší, jejich širší použití však omezuje vysoká cena. Azolová skupina (ketokonazol, flukonazol, itrakonazol) dnes představuje nejšířeji používanou skupinu antimykotik, triazoly 3. generace (vorikonazol, posakonazol, ravukonazol) rozšiřují spektrum účinku se zaměřením zejména na aspergilové infekce. Perspektivou budou preparáty s jinou cílovou strukturou zásahu. Podle mechanizmu účinku jde o echinokandiny (inhibice syntézy b-glukanu), nikkomyciny (inhibitory syntézy chitinu), sordariny (selektivní inhibitory proteosyntézy), pradimiciny (lýza buněk vazbou na manoproteiny) a zvýšený nárůst rezistence by měly ovlivnit inhibitory efluxní pumpy (milbemycin). Ve všech těchto případech probíhají klinické studie, u některých již 3. fáze.
Spectrum of antimycotics used in treatment of systemic mycoses is comparatively poor. The oldest and till present received „golden standard“ is polyen amphotericin B (AmB). It has the widest spectrum of effects and has the lowest incidence of resistances. However, the therapy can be accompanied by manifestations of toxicity, namely that of nephrotoxicity. „Lipoid“ form of AmB (Abelcet, Amphocil, AmBisome) with only 20% risk of nephrotoxicity partly solved the problem. Wider use of these drugs is hindered by their high price. The azoles group (ketoconazole, fluconazole, itraconazole) today represents the most frequently used group of antimycotics; triazols of the 3rd generation (variconazole, posaconazole, ravuconazole) broaden the spectrum of effects namely to aspergil infections. In the future substances with a different target structure will be used. According the mechanism of effect they can be classified as echinocandins (inhibition of b-glucane synthesis), echinocandins (inhibition of chitin synthesis), sordarines (selective inhibitors of proteosynthesis), pradimicines (cell lysis by binding on manoproteins). The rising occurrence of resistance should be coped with inhibitors of the efflux pump (milbemycine). Clinical testing of all these substances is already in progress, in some of them already in phase III.
This study was designed to evaluate the prevalence of antifungal resistance, genetic mechanisms associated with in vitro induction of azole and echinocandin resistance and genotyping of Candida krusei, which is intrinsically resistant to fluconazole and is recovered from clinical and nonclinical sources from different countries. Our results indicated that all the isolates were susceptible or had the wild phenotype (WT) to azoles, amphotericin B, and only 1.27% showed non-WT for flucytosine. Although 70.88% of the isolates were resistant to caspofungin, none of them were categorized as echinocandin-resistant as all were susceptible to micafungin and no FKS1 hot spot 1 (HS1) or HS2 mutations were detected. In vitro induction of azole and echinocandin resistance confirmed the rapid development of resistance at low concentrations of fluconazole (4 μg/ml), voriconazole (0.06 μg/ml), and micafungin (0.03 μg/ml), with no difference between clinical and nonclinical isolates in the resistance development. Overexpression of ABC1 gene and FKS1 HS1 mutations were the major mechanisms responsible for azole and echinocandin resistance, respectively. Genotyping of our 79 isolates coupled with 217 other isolates from different sources and geography confirmed that the isolates belong to two main subpopulations, with isolates from human clinical material and Asia being more predominant in cluster 1, and environmental and animals isolates and those from Europe in cluster 2. Our results are of critical concern, since realizing that the C. krusei resistance mechanisms and their genotyping are crucial for guiding specific therapy and for exploring the potential infection source.
- MeSH
- antifungální látky farmakologie terapeutické užití MeSH
- azoly * farmakologie MeSH
- echinokandiny * farmakologie MeSH
- fungální léková rezistence genetika MeSH
- genotyp MeSH
- mikrobiální testy citlivosti MeSH
- Pichia MeSH
- prevalence MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Systemic fungal diseases and antifungal resistance represent a serious problem in human medicine and con-tribute to increased patient mortality. The most common causes of these diseases are opportunistic yeasts of the genus Candida. C. albicansis considered to be the main pathogen, together with C. glabrata, C. tropicalis, C. par-apsilosis, and C.krusei. Azole antifungals predominate in the treatment of the systemic mycoses. For antifungal re-sistance in Candidaspp. some genes and their mutations are responsible, the genes ERG11, CDR1, CDR2and MDR1being considered the most important. The main target of azole antifungals is the process of ergosterol syn-thesis. Due to ergosterol crucial functions and its unique structural properties, the synthesis of ergosterol and its individual steps represent the target of most clinically available antifungals. The biofilm appears to be a signifi-cant virulence factor of the yeast Candidaspp. It allows hematogenous dissemination of cells, prevents the effect of antifungals on all cells during treatment and leads to a high level of antimicrobial resistance. The antifungal re-sistance in candidiasis often has a multifactorial origin, which must be considered in the treatment of systemic mycoses and in the development of new antifungals.
- MeSH
- antifungální látky chemie farmakologie terapeutické užití MeSH
- azoly farmakologie terapeutické užití MeSH
- biofilmy účinky léků MeSH
- Candida patogenita účinky léků MeSH
- ergosterol biosyntéza MeSH
- faktory virulence MeSH
- flukonazol farmakologie terapeutické užití MeSH
- fungální léková rezistence MeSH
- itrakonazol farmakologie terapeutické užití MeSH
- kandidóza * farmakoterapie mikrobiologie MeSH
- lidé MeSH
- vorikonazol farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
