Cryptococcus neoformans Dotaz Zobrazit nápovědu
Cryptococcosis is an invasive mycosis caused mainly by Cryptococcus gattii and C. neoformans and is treated with amphotericin B (AMB), fluconazole and 5-fluorocytosine. However, antifungal resistance, limited and toxic antifungal arsenal stimulate the search for therapeutic strategies such as drug repurposing. Among the repurposed drugs studied, the selective serotonin reuptake inhibitors (SSRIs) have shown activity against Cryptococcus spp. However, little is known about the antifungal effect of duloxetine hydrochloride (DH), a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), against C. neoformans and C. gattii. In this study, DH inhibited the growth of several C. neoformans and C. gattii strains at concentrations ranging from 15.62 to 62.50 μg/mL. In addition, DH exhibited fungicidal activity ranging from 15.62 to 250 μg/mL. In biofilm, DH treatment reduced Cryptococcus spp. biomass at a level comparable to AMB, with a significant reduction (85%) for C. neoformans biofilms. The metabolic activity of C. neoformans and C. gattii biofilms decreased significantly (99%) after treatment with DH. Scanning electron micrographs confirmed the anti-biofilm activity of DH, as isolated cells could be observed after treatment. In conclusion, DH showed promising antifungal activity against planktonic cells and biofilms of C. neoformans and C. gattii, opening perspectives for further studies with DH in vivo.
- MeSH
- antifungální látky * farmakologie MeSH
- biofilmy * účinky léků MeSH
- Cryptococcus gattii * účinky léků MeSH
- Cryptococcus neoformans * účinky léků růst a vývoj MeSH
- duloxetinum hydrochlorid * farmakologie MeSH
- kryptokokóza farmakoterapie mikrobiologie MeSH
- mikrobiální testy citlivosti * MeSH
- Publikační typ
- časopisecké články MeSH
Infekcie, ktorých póvodcom je Cryptococcus neoformans, sa vyskytujú převážné u pacientov s poruchami funkcie T-lymfocytov, a najma u osob s AIDS.Autoři sa domnievajú, že touto infekciou sú ohrození tiež fudia vyššieho veku, a to aj relativné zdraví. Zaznamenali fatálnu kryptokokovú meningoencefalitídu s fulminantným priebehom u 76-ročnej pacientky bez prejavov imunodeficitu v anamnéze.
Infections caused by Cryptococcus neoformans affect mainly patients with impaired functions oř T-cells, and in particular individuals with AIDS.The authors suppose also older subjects in relatively good health to be endangered by this infection. A čase of fatal cryptococcal meningoencephalitis with fulminant coarse was detected in a 76-year female patient without evident immunodeficiency.
- MeSH
- Cryptococcus neoformans izolace a purifikace patogenita MeSH
- dospělí MeSH
- imunitní systém patologie MeSH
- infekce dýchací soustavy MeSH
- kryptokoková meningitida etiologie patologie terapie MeSH
- lidé MeSH
- meningoencefalitida etiologie patologie terapie MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
BACKGROUND: Cryptococcus neoformans is an obligate aerobic pathogenic yeast causing lung infection typically followed by spread to the central nervous system. During pathogenesis, it relies on well-established virulence factors. This review focuses on the emerging role of cryptococcal adaptation to hypoxia in pathogenesis. METHODS AND RESULTS: We examined the MedLine database for information on the cryptococcal hypoxia response. While several recent papers describe components of two presumable hypoxia-sensing pathways including description of their target genes, a link of this system to the hypoxic tuning of proliferation is still missing. In addition, an interpretation of this knowledge in respect to the general picture of microbial pathogenesis is lacking. CONCLUSIONS: There seems to be a striking parallel between biofilm formation in bacteria, which results in chronic dormant infection with the potential for acute outbreaks, and the dormant state of primary infection followed by secondary outbreaks in C. neoformans. We propose a hypothesis that cryptococcal response to hypoxia might be the driving force for developing a state of dormant infection which is characterized by slowed proliferation and extensive changes in transcriptome and phenotype. This state enables C. neoformans to survive in host and possibly develop life-threatening acute outbreaks later. Hence, conventional well-aerated planktonic culture is not a good in vitro model for studying the pathogenesis of infection and we advocate the development of a more adequate model. Our further conclusion is that the ability of the immune system and antifungal agents to cope with hypoxia-adapted cells is crucial for the successful eradication of cryptococcal infection.
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
Cryptococcus neoformans is an opportunistic fungal pathogen that can cause life-threatening invasive fungal infections. As its prevalence and drug resistance continue to rise, cryptococcosis requires new treatment options. Tapping into the potential antifungal effects of traditional drugs or combination therapy has become one of the options. This study was the first to examine the interaction of hydroxychloroquine (HCQ) and itraconazole (ITR) on Cryptococcus neoformans in vitro and in vivo. Our results showed that HCQ alone and in combination with ITR exhibited antifungal activity against C. neoformans planktonic cells. When HCQ was combined with ITR, the minimal inhibitory concentration (MIC) value of HCQ decreased to 32 μg/mL, and the MIC value of ITR decreased from 0.25 μg/mL to 0.06-0.25 μg/mL. The time-killing curve showed that the combined application of HCQ and ITR significantly shortened the killing time, dynamically defining the antifungal activity. The minimum biofilm clearance concentration (MBEC) of HCQ was only 32 μg/mL, which was significantly lower than the MIC of HCQ for planktonic cells. When combined with ITR, the MBEC of ITR decreased from 128 μg/mL to 2-1 μg/mL, and the MBEC of HCQ decreased from 32 μg/mL to 4 μg/mL, indicating a synergistic antifungal biofilm effect. In comparison to ITR alone, the combination of HCQ and ITR treatment increased the survival of C. neoformans-infected Galleria mellonella larvae and decreased the fungal burden of infected larvae. Mechanistic investigations revealed that HCQ might damage C. neoformans cell membranes, impact the structure of fungal cells, cause extracellular material leakage, and have a potent affinity for attaching to the C. neoformans genomic DNA. In conclusion, HCQ has potential clinical application in the treatment of cryptococcosis.
- MeSH
- antifungální látky farmakologie terapeutické užití MeSH
- Cryptococcus neoformans * MeSH
- hydroxychlorochin farmakologie terapeutické užití MeSH
- itrakonazol farmakologie MeSH
- kryptokokóza * farmakoterapie mikrobiologie MeSH
- mikrobiální testy citlivosti MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
