Dataset Information

In vitro biological activity and structural analysis of 2,4-diamino-5-(2'-arylpropargyl)pyrimidine inhibitors of Candida albicans.

ABSTRACT: In order to develop new antifungal agents effective against two species of Candida, we have designed a series of dihydrofolate reductase (DHFR) inhibitors. Here, we explore the structure-activity relationships of these inhibitors toward Candida albicans DHFR by evaluating enzyme inhibition, antifungal activity and toxicity to mammalian cells. Analysis of docked complexes of the enzyme and inhibitors yields the structural basis of relative potency. The meta-biphenyl series of this class exhibits the greatest enzyme inhibition, selectivity and antifungal activity.

SUBMITTER: Paulsen JL

PROVIDER: S-EPMC2724765 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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In vitro biological activity and structural analysis of 2,4-diamino-5-(2'-arylpropargyl)pyrimidine inhibitors of Candida albicans.

Paulsen Janet L JL Liu Jieying J Bolstad David B DB Smith Adrienne E AE Priestley Nigel D ND Wright Dennis L DL Anderson Amy C AC

Bioorganic & medicinal chemistry 20090617 14

In order to develop new antifungal agents effective against two species of Candida, we have designed a series of dihydrofolate reductase (DHFR) inhibitors. Here, we explore the structure-activity relationships of these inhibitors toward Candida albicans DHFR by evaluating enzyme inhibition, antifungal activity and toxicity to mammalian cells. Analysis of docked complexes of the enzyme and inhibitors yields the structural basis of relative potency. The meta-biphenyl series of this class exhibits ...[more]

PMID: 19560363

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Project description:The dimorphic fungus Candida albicans is one of the most important opportunistic pathogens for humankind. The use of fungicides against Candida could be associated with sub-inhibitory effects, which are referred to as fungal stress responses and are undesirable for the host. In this work, we investigated the antifungal action of 2,4-diacetylphloroglucinol (2,4-DAPG) against Candida albicans ATCC 10231 with a focus on their biofilm-forming ability. We found that 2,4-DAPG was able to reduce the ability of Candida cells to form biofilms, but complete inhibition and eradication effects were not achieved. Furthermore, C. albicans cells in the adherent state were characterized by reduced susceptibility to 2,4-DAPG compared to planktonic cells. The investigation of the mechanisms that could explain the antibiofilm action of 2,4-DAPG revealed a reduction in the cell`s surface hydrophobicity and the inhibition of the yeast-to-hyphae transition. The inhibition of the Candida cells filamentation was accompanied by an increase in the expression of the NRG1 gene, which is a negative regulator of hyphal development. In addition, we microscopically visualized the treated biofilms and revealed numerous channels that were decorated with particles and localized on the hyphae. We assumed that these hyphal structures could be associated with the secretion of aspartyl proteases (Sap). The performed assessments revealed an increase in the activity of Sap, which was accompanied by an increase in the expression of the sap2 and sap4 genes. The antifungal action of 2,4-DAPG is known to be associated with affecting the permeability of cellular structures, which leads to H+ATPase malfunction and the disruption of mitochondrial respiration. The subsequent cytosol acidification and generation of ROS trigger the inhibition of Candida filamentation and activation of Sap production. The introduction of antioxidant Trolox simultaneously with 2,4-DAPG leads to a reduction in Sap production. Collectively, the obtained data indicate new aspects of the interaction of fungal cells with 2,4-DAPG, an antimicrobial metabolite of Pseudomonas spp.

Dataset Information

In vitro biological activity and structural analysis of 2,4-diamino-5-(2'-arylpropargyl)pyrimidine inhibitors of Candida albicans.

Publications

In vitro biological activity and structural analysis of 2,4-diamino-5-(2'-arylpropargyl)pyrimidine inhibitors of Candida albicans.

Similar Datasets

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