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Loureirin A is a major active component of Draconis sanguis, a traditional Chinese medicine. This work aimed to investigate the activity of loureirin A against Candida albicans biofilms. 2, 3-Bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT)reduction assay and scanning electron microscopy were used to investigate the anti-biofilm effect. Minimal inhibitory concentration testing and time-kill curve assay were used to evaluate fungicidal activity. Cell surface hydrophobicity (CSH) assay and hyphal formation experiment were respectively carried out to investigate adhesion and morphological transition, two virulence traits of C. albicans. Real-time RT-PCR was used to investigate gene expression. Galleria mellonella-C. albicans and Caenorhabditis elegans-C. albicans infection models were used to evaluate the in-vivo antifungal effect. Human umbilical vein endothelial cells and C. elegans nematodes were used to evaluate the toxicity ofloureirin A. Our data indicated that loureirin A had a significant effect on inhibiting C. albicans biofilms, decreasing CSH, and suppressing hyphal formation. Consistently, loureirin A down-regulated the expression of some adhesion-related genes and hypha/biofilm-related genes. Moreover, loureirin A prolonged the survival of Galleria mellonella and Caenorhabditis elegans in C. albicans infection models and exhibited low toxicity. Collectively, loureirin A inhibits fungal biofilms, and this effect may be associated with the suppression of pathogenic traits, adhesion and hyphal formation.
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The incidence of systemic fungal infections have increased dramatically, moreover, drug resistance including either primary (intrinsic) or secondary (acquired) resistance, becomes one of the main reasons accounting for the failure of treating invasive fungal infections in the past decades. Nowadays, clinically available antifungal drugs are limited and their combination in antifungal therapy was not effective. It is expected to be a new strategy to synergistically sensitize antifungal drugs against drug-resistant fungi by using new small molecules. Based on the study in our research group and the reported work of others, we reviewed the research of the natural products which have synergistic effect with the antifungal agents against drug-resistant fungi. This review focused on the resource, structure, pharmacological activity, and action mechanism of the compounds, as well as somewhat in common, and would provide theoretical base for seeking new drug against drug-resistance fungi.
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Antifúngicos , Química , Farmacología , Productos Biológicos , Química , Farmacología , Sinergismo Farmacológico , HongosRESUMEN
Abstract: Our previous work revealed berberine can significantly enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans, which suggested that berberine has synergistic antifungal activity with fluconazole. Preliminary SAR of berberine needs to be studied for the possibility of investigating its target and SAR, improving its drug-likeness, and exploring new scaffold. In this work, 13-substitutited benzyl berberine derivatives and N-benzyl isoquinoline analogues were synthesized and characterized by 1H NMR and MS. Their synergetic activity with fluconazole against fluconazole-resistant Candida albicans was evaluated in vitro. The 13-substitutited benzyl berberine derivatives 1a-1e exhibited comparable activity to berberine, which suggested that the introduction of functional groups to C-13 can maintain its activity. The N-benzyl isoquinolines, which were designed as analogues of berberine with its D ring opened, exhibited lower activity than berberine. However, compound 2b, 2c, and 4b showed moderate activity, which indicated that berberine may be deconstructed to new scaffold with synergistic antifungal activity with fluconazole. The results of our research may be helpful to the SAR studies on its other biological activities.
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Antifúngicos , Farmacología , Berberina , Farmacología , Candida albicans , Farmacorresistencia Fúngica , Sinergismo Farmacológico , Fluconazol , Farmacología , Isoquinolinas , Farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
Gene mutation of Candida albicans is one of the main causes for azole drug resistance. Different types of variation play different roles in promoting the process of drug resistance. ERG series of gene mutations primarily affect the ergosterol synthesis pathway. When the regulatory factors TAC1 for CDR1 gene and Mrr1 for MDR1 gene generate mutations, the expression level of drug efflux pump protein in Candida albicans may be changed. In addition, gene copy number variation is also gaining attention. Therefore, the research of mutation resistance-associated genes has a positive meaning to explore the mechanism of drug resistance in Candida albicans.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Genética , Antifúngicos , Farmacología , Azoles , Farmacología , Candida albicans , Genética , Sistema Enzimático del Citocromo P-450 , Genética , Variaciones en el Número de Copia de ADN , Farmacorresistencia Fúngica , Proteínas Fúngicas , Genética , Proteínas de Transporte de Membrana , Genética , Mutación , GenéticaRESUMEN
Polyamides, containing N-methylpyrrole (Py) and N-methyl-imidazole (Im) amino acids, are synthetic oligomers programmed to read the DNA double helix in the minor groove with high affinities and sequence specificities resulting in modulation of gene expression. They are cell permeable, stable and have no cytotoxicity, which provide a promising tool of gene regulation. We describe here recent advances in the field of DNA binding polyamides, including pairing rules, specifities and affinities to DNA, synthesis methods, cellular and nuclear uptake properties, gene regulation and effectiveness in vivo. The potential problems and difficulties in future research are also discussed.
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Animales , Emparejamiento Base , ADN , Química , Genética , Huella de ADN , Regulación de la Expresión Génica , Imidazoles , Química , Metabolismo , Farmacología , Nylons , Química , Metabolismo , Farmacología , Pirroles , Química , Metabolismo , FarmacologíaRESUMEN
Objective To explore the relationship between fluconazole resistance and expression of multidrug resistant protein genes,including CDR1,CDR2,MDRI.Methods The total RNA was extracted from fluconazole-resistant and -susceptible Candida albicans isolates,and cDNA was synthesized.The expression of CDR1,CDR2 and MDRl genes was then detected by quantitative real-time PCR.The?CT (threshold cycle) value was obtained by subtracting the CT value of 18S rRNA from that of the targeted gene.Results The?CT value of CDR2 was significantly lower in fluconazole-resistant isolates than in fluconazole- susceptible isolates (7.52?2.53 vs.9.28?3.15,t=2.367,P