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Design and synthesis of new drugs inhibitors of Candida albicans hyphae and biofilm formation by upregulating the expression of TUP1 transcription repressor gene.

ABSTRACT: Candida albicans is a common human fungal pathogen that causes disease ranging from superficial to lethal infections. C. albicans grows as budding yeast which can transform into hyphae in response to various environmental or biological stimuli. Although both forms have been associated with virulence, the hyphae form is responsible for the formation of multi-drug resistance biofilm. Here, new compounds were designed to selectively inhibit C. albicans hyphae formation without affecting human cells to afford sufficient safety. The newly designed 5-[3-substitued-4-(4-substituedbenzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one derivatives, named SR, showed very specific and effective inhibition activity against C. albicans hyphae formation. SR compounds caused hyphae inhibition activity at concentrations 10-40 fold lower than the concentration required to inhibit Candida yeast and bacterial growths. The anti-hyphae inhibition activities of SR compounds were via activation of the hyphae transcription repressor gene, TUP1. Correlation studies between the expression of TUP1 gene and the activity of SR compounds confirmed that the anti-C. albicans activities of SR compounds were via inhibition of hyphae formation. The newly designed SR compounds showed 10-40% haemolytic activity on human erythrocytes when compared to 100% haemolysis by 0.1% triton employed as positive control. Furthermore, theoretical prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) of SR compounds confirmed their safety, efficient metabolism and possible oral bioavailability. With the minimal toxicity and significant activity of the newly-designed SR compounds, a future optimization of pharmaceutical formulation may develop a promising inhibitor of hyphal formation not only for C. albicans but also for other TUP1- dependent dimorphic fungal infections.

SUBMITTER: Hamdy R

PROVIDER: S-EPMC8569251 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:TUP1 is a well-characterized repressor of transcription in Saccharomyces cerevisiae and Candida albicans and is observed as a single-copy gene. We observe that most species that experienced a whole-genome duplication outside of the Saccharomyces genus have two copies of TUP1 in the Saccharomycotina yeast clade. We focused on Candida glabrata and demonstrated that the uncharacterized TUP1 homolog, C. glabrata TUP11 (CgTUP11), is most like the S. cerevisiae TUP1 (ScTUP1) gene through phenotypic assays and transcriptome sequencing (RNA-seq). Whereas CgTUP1 plays a role in gene repression, it is much less repressive in standard growth media. Through RNA-seq and reverse transcription-quantitative PCR (RT-qPCR), we observed that genes associated with pathogenicity (YPS2, YPS4, and HBN1) are upregulated upon deletion of either paralog, and loss of both paralogs is synergistic. Loss of the corepressor CgCYC8 mimics the loss of both paralogs, but not to the same extent as the Cgtup1Δ Cgtup11Δ mutant for these pathogenesis-related genes. In contrast, genes involved in energy metabolism (CgHXT2, CgADY2, and CgFBP1) exhibit similar behavior (dependence on both paralogs), but deletion of CgCYC8 is very similar to the Cgtup1Δ Cgtup11Δ mutant. Finally, some genes (CgMFG1 and CgRIE1) appear to only be dependent on CgTUP11 and CgCYC8 and not CgTUP1. These data indicate separable and overlapping roles for the two TUP1 paralogs and that other genes may function as the CgCyc8 corepressor. Through a comparison by RNA-seq of Sctup1Δ, it was found that TUP1 homologs regulate similar genes in the two species. This work highlights that studies focused only on Saccharomyces may miss important biological processes because of paralog loss after genome duplication. IMPORTANCE Due to a whole-genome duplication, many yeast species related to C. glabrata have two copies of the well-characterized TUP1 gene, unlike most Saccharomyces species. This work identifies roles for the paralogs in C. glabrata, highlights the importance of the uncharacterized paralog, called TUP11, and suggests that the two paralogs have both overlapping and unique functions. The TUP1 paralogs likely influence pathogenicity based on tup mutants upregulating genes that are associated with pathogenicity.

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Design and synthesis of new drugs inhibitors of Candida albicans hyphae and biofilm formation by upregulating the expression of TUP1 transcription repressor gene.

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