Cryptococcus neoformans is an encapsulated yeast that can cause cryptococcosis and cryptococcal meningitis, which conventional treatment involves antifungal drugs such as polyenes, flucytosine, azoles, and their combinations. However, the high cost, toxicity, and increase in fungi resistance to antifungal agents stimulate the search for therapeutic strategies such as drug repurposing and combination therapy. This study evaluated the activity of the antihypertensive verapamil (VEH) alone and combined with amphotericin B (AmB) against C. neoformans. VEH exhibited antifungal activity against C. neoformans with minimum inhibitory concentration and minimum fungicidal concentration of 118 μg per mL. The combination of VEH and AmB exhibited synergism, reducing at least eightfold both drugs' concentrations. Moreover, the combination decreased the size and glucuronoxylomannnan content of C. neoformans capsule. However, no difference was observed in ergosterol levels of C. neoformans after treatment with VEH and AmB in combination. Altogether, VEH in combination with AmB exhibits potential as a candidate as for the development of anti-cryptococcal drug.
- MeSH
- amfotericin B farmakologie terapeutické užití MeSH
- antifungální látky farmakologie terapeutické užití MeSH
- Cryptococcus neoformans * MeSH
- flucytosin farmakologie terapeutické užití MeSH
- kryptokokóza * farmakoterapie mikrobiologie MeSH
- mikrobiální testy citlivosti MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- amfotericin B farmakologie terapeutické užití MeSH
- antifungální látky farmakologie terapeutické užití MeSH
- COVID-19 * komplikace terapie MeSH
- dospělí MeSH
- lidé MeSH
- septický šok MeSH
- umělé dýchání škodlivé účinky MeSH
- ventilátorová pneumonie etiologie terapie MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- MeSH
- akutní myeloidní leukemie farmakoterapie MeSH
- amfotericin B aplikace a dávkování farmakologie MeSH
- antifungální látky MeSH
- dítě MeSH
- febrilní neutropenie farmakoterapie komplikace MeSH
- hematologické nádory farmakoterapie komplikace MeSH
- indukční chemoterapie MeSH
- invazivní mykotické infekce farmakoterapie MeSH
- kandidóza farmakoterapie MeSH
- lidé MeSH
- oportunní infekce MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
There are only a few antifungal drugs used systemically in treatment, and invasive fungal infections that are resistant to these drugs are an emerging problem in health care. In this study, we performed a high-copy-number genomic DNA (gDNA) library screening to find and characterize genes that reduce susceptibility to amphotericin B, caspofungin, and voriconazole in Saccharomyces cerevisiae We identified the PDR16 and PMP3 genes for amphotericin B, the RMD9 and SWH1 genes for caspofungin, and the MRS3 and TRI1 genes for voriconazole. The deletion mutants for PDR16 and PMP3 were drug susceptible, but the other mutants had no apparent susceptibility. Quantitative-PCR analyses suggested that the corresponding drugs upregulated expression of the PDR16, PMP3, SWH1, and MRS3 genes. To further characterize these genes, we also profiled the global expression patterns of the cells after treatment with the antifungals and determined the genes and paths that were up- or downregulated. We also cloned Candida albicans homologs of the PDR16, PMP3, MRS3, and TRI1 genes and expressed them in S. cerevisiae Heterologous expression of Candida homologs also provided reduced drug susceptibility to the budding yeast cells. Our analyses suggest the involvement of new genes in antifungal drug resistance.
- MeSH
- amfotericin B farmakologie MeSH
- antifungální látky farmakologie MeSH
- Candida albicans účinky léků genetika metabolismus MeSH
- fungální léková rezistence genetika MeSH
- kaspofungin farmakologie MeSH
- mikrobiální testy citlivosti MeSH
- Saccharomyces cerevisiae - proteiny genetika metabolismus MeSH
- Saccharomyces cerevisiae účinky léků genetika metabolismus MeSH
- Saccharomycetales účinky léků genetika metabolismus MeSH
- vorikonazol farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Microorganisms that cause chronic infections exist predominantly as surface-attached stable communities known as biofilms. Microbial cells in biofilms are highly resistant to conventional antibiotics and other forms of antimicrobial treatment; therefore, modern medicine tries to develop new drugs that exhibit anti-biofilm activity. We investigated the influence of a plant polyphenolic compound resveratrol (representative of the stilbene family) on the opportunistic pathogen Trichosporon cutaneum. Besides the influence on the planktonic cells of T. cutaneum, the ability to inhibit biofilm formation and to eradicate mature biofilm was studied. We have tested resveratrol as pure compound, as well as resveratrol in complex plant extract-the commercially available dietary supplement Regrapex-R-forte, which contains the extract of Vitis vinifera grape and extract of Polygonum cuspidatum root. Regrapex-R-forte is rich in stilbenes and other biologically active substances. Light microscopy imaging, confocal microscopy, and crystal violet staining were used to quantify and visualize the biofilm. The metabolic activity of biofilm-forming cells was studied by the tetrazolium salt assay. Amphotericin B had higher activity against planktonic cells; however, resveratrol and Regrapex-R-forte showed anti-biofilm effects, both in inhibition of biofilm formation and in the eradication of mature biofilm. The minimum biofilm eradicating concentration (MBEC80) for Regrapex-R-forte was found to be 2222 mg/L (in which resveratrol concentration is 200 mg/L). These methods demonstrated that Regrapex-R-forte can be employed as an anti-biofilm agent, as it has similar effect as amphotericin B (MBEC80 = 700 mg/L), which is routinely used in clinical practice.
- MeSH
- amfotericin B farmakologie MeSH
- antifungální látky farmakologie MeSH
- biofilmy účinky léků růst a vývoj MeSH
- mikrobiální testy citlivosti MeSH
- resveratrol farmakologie MeSH
- Reynoutria japonica chemie MeSH
- rostlinné extrakty farmakologie MeSH
- Trichosporon účinky léků růst a vývoj metabolismus MeSH
- Vitis chemie MeSH
- Publikační typ
- časopisecké články MeSH
Mukormykózy jsou velmi závažné, agresivně probíhající houbové infekce vyskytující se ve vysokém procentu u pacientů s modifikovanou imunitní odpovědí. Jejich mortalita může dosahovat při generalizaci onemocnění až 96 %. Základem dosažení co nejlepšího klinického výsledku je časná diagnostika a razantní terapie (antimykotická, případně v kombinaci s chirurgickou). Prezentovaný klinický případ poukazuje na význam načasování zahájení terapie, přestože ani včasná adekvátní terapie nemusí být vždy spojena s přežitím.
Mucormycosis is a very serious, invasive fungal infection, occurring frequently in patients with a modified immune response. Mortality in cases of a generalized form of mucormycosis can reach 96 %. The principles of successful treatment of this disease are early diagnosis and aggressive antimycotic and/or surgical therapy. In this case report we point out the clinical importance of correct timing of therapy, even though even early and appropriate management does not always guarantee survival.
- MeSH
- amfotericin B aplikace a dávkování farmakologie terapeutické užití MeSH
- antifungální látky terapeutické užití MeSH
- intravenózní podání metody MeSH
- lidé MeSH
- mukormykóza * diagnóza mortalita terapie MeSH
- polymerázová řetězová reakce metody MeSH
- pooperační komplikace MeSH
- senioři MeSH
- smrt MeSH
- transplantace orgánů MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- práce podpořená grantem MeSH
Candida albicans is the main causative agent of vulvovaginal candidiasis (VVC), a common mycosis in women, relapses of which are difficult to manage due to biofilm formation. This study aimed at developing novel non-toxic compounds active against Candida spp. biofilms. We synthesised analogues of natural antifungal peptides LL-III (LL-III/43) and HAL-2 (peptide VIII) originally isolated from bee venoms and elucidated their structures by nuclear magnetic resonance spectroscopy. The haemolytic, cytotoxic, antifungal and anti-biofilm activities of LL-III/43 and peptide VIII were then tested. LL-III/43 and VIII showed moderate cytotoxicity to HUVEC-2 cells and had comparable inhibitory activity against C. albicans and non-albicans spp. The lowest minimum inhibitory concentration (MIC90) of LL-III/43 was observed towards Candida tropicalis (0.8 µM). That was 8-fold lower than that of antimycotic amphotericin B. Both peptides can be used to inhibit Candida spp. bio film f ormation. Biofilm inhibitory concentrations (BIC50) ranged from 0.9 to 58.6 µM and biofilm eradication concentrations (BEC50) for almost all tested Candida spp. strains ranged from 12.8 to 200 µM. Als o pro ven were the peptides' abilities to reduce the area colonised by biofilms , inhibit hyphae formation and permeabilise cell membranes in biofil ms . LL-III/43 and VIII are promising candidates for further development as therapeutics against VVC.
- MeSH
- amfotericin B farmakologie MeSH
- antifungální látky chemická syntéza farmakologie MeSH
- biofilmy účinky léků MeSH
- Candida účinky léků MeSH
- endoteliální buňky pupečníkové žíly (lidské) účinky léků MeSH
- hyfy účinky léků MeSH
- kandidóza vulvovaginální mikrobiologie MeSH
- kationické antimikrobiální peptidy chemická syntéza farmakologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- včelí jedy chemie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Trichosporon cutaneum is the second most significant opportunistic pathogen of genus Trichosporon after T. asahii . Its virulence is strongly tied to biofilm formation and colonization of various medical materials. Tricho- sporon spp. infections are ordinarily treated with antifun- gal azoles or polyene antibiotics. Nowadays, this type of therapy often fails and there is a great effort aimed at find- ing new antimicrobial substances, often originating from plant sources. These sources are frequently used as the components of traditional medicine. This study is focused on the effect of antibiotic am- photericin B, polysaccharide chitosan, and flavonoid bai- calein on the biofilm formation of T. cutaneum CCY 30-5-10. Their effects were studied by inverse microscope Cel- lavista using the image analysis evaluation of the area colonized by the biofilm in 96well microtitre plates. Baicalein was the most effective substance (concentration 40 mg L ‒ 1 caused 50% inhibition of cell adhesion and 75% eradication of mature biofilm). A significant effect was also observed when chitosan was applied (concentration 40 mg L ‒ 1 caused 69% inhibition of cell adhesion). Polyene antibiotic amphotericin B had distinctly stimulating effect on cell adhesion and only slightly eradicated the mature biofilm of T. cutaneum CCY 30-5-10.
- Klíčová slova
- Baicalein,
- MeSH
- amfotericin B aplikace a dávkování farmakologie MeSH
- antifungální látky aplikace a dávkování farmakologie MeSH
- antitumorózní látky aplikace a dávkování farmakologie MeSH
- biofilmy účinky léků MeSH
- chitosan aplikace a dávkování farmakologie MeSH
- flavanony aplikace a dávkování farmakologie MeSH
- Trichosporon patogenita účinky léků MeSH
- Publikační typ
- práce podpořená grantem MeSH
Due to the increasing number of Candida albicans' infections and the resistance of this pathogenic fungus to drugs, new therapeutic strategies are sought. One of such strategies may be the use of static magnetic field (SMF). C. albicans cultures were subjected to static magnetic field of the induction 0.5 T in the presence of fluconazole and amphotericin B. We identified a reduction of C. albicans hyphal length. Also, a statistically significant additional effect on the viability of C. albicans was revealed when SMF was combined with the antimycotic drug amphotericin B. The synergistic effect of this antimycotic and SMF may be due to the fact that amphotericin B binds to ergosterol in plasma membrane and SMF similarly to MF could influence domain orientation in plasma membrane (PM).
- MeSH
- amfotericin B farmakologie MeSH
- antifungální látky farmakologie MeSH
- Candida albicans účinky léků růst a vývoj MeSH
- flukonazol farmakologie MeSH
- hyfy účinky léků růst a vývoj MeSH
- magnetické pole * MeSH
- mikrobiální testy citlivosti MeSH
- mikrobiální viabilita účinky léků MeSH
- Publikační typ
- časopisecké články MeSH
Flavonolignans from the seeds of the milk thistle (Silybum marianum) have been extensively used in folk medicine for centuries. Confirmation of their properties as hepatoprotective, antioxidant and anticancer has been obtained using standardized extracts and purified flavonolignans. Information on their potential effect on Leishmania is very scarce. We have investigated the effect of silymarin, silybin and related flavonolignans on the multiplication of promastigotes in vitro and ex vivo on intracellular amastigotes of L. infantum (Li) and L. donovani (Ld), causative agents of human and canine visceral leishmaniasis (VL). In addition, the potential synergistic effect of the most active molecule and well-established antileishmanial drugs against promastigotes was explored. Dehydroisosilybin A elicited the highest inhibition against Ld and Li promastigotes with an approximate IC50 of 90.23 µM. This molecule showed a moderate synergism with amphotericin B (AmB) but not with SbIII or paromomycin, although it was ineffective against amastigotes. Antileishmanial activity on intracellular amastigotes of the two diastereoisomers of dehydrosilybin (10 µM) was comparable to that elicited by 0.1 µM AmB. Antiproliferative activity and safety of flavonolignans suggest the interest of exploring their potential value in combination therapy against VL.
- MeSH
- amfotericin B farmakologie MeSH
- antiprotozoální látky farmakologie MeSH
- Leishmania donovani účinky léků MeSH
- Leishmania infantum účinky léků MeSH
- leishmanióza viscerální metabolismus MeSH
- lidé MeSH
- psi MeSH
- silibinin MeSH
- silymarin farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
