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Antifungal Agent 4-AN Changes the Genome-Wide Expression Profile, Downregulates Virulence-Associated Genes and Induces Necrosis in Candida albicans Cells.

ABSTRACT: In the light of the increasing occurrence of antifungal resistance, there is an urgent need to search for new therapeutic strategies to overcome this phenomenon. One of the applied approaches is the synthesis of small-molecule compounds showing antifungal properties. Here we present a continuation of the research on the recently discovered anti-Candida albicans agent 4-AN. Using next generation sequencing and transcriptional analysis, we revealed that the treatment of C. albicans with 4-AN can change the expression profile of a large number of genes. The highest upregulation was observed in the case of genes involved in cell stress, while the highest downregulation was shown for genes coding sugar transporters. Real-time PCR analysis revealed 4-AN mediated reduction of the relative expression of genes engaged in fungal virulence (ALS1, ALS3, BCR1, CPH1, ECE1, EFG1, HWP1, HYR1 and SAP1). The determination of the fractional inhibitory concentration index (FICI) showed that the combination of 4-AN with amphotericin B is synergistic. Finally, flow cytometry analysis revealed that the compound induces mainly necrosis in C. albicans cells.

SUBMITTER: Martyna A

PROVIDER: S-EPMC7356344 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Antifungal Agent 4-AN Changes the Genome-Wide Expression Profile, Downregulates Virulence-Associated Genes and Induces Necrosis in Candida albicans Cells.

Martyna Aleksandra A Masłyk Maciej M Janeczko Monika M Kochanowicz Elżbieta E Gielniewski Bartłomiej B Świercz Aleksandra A Demchuk Oleg M OM Kubiński Konrad K

Molecules (Basel, Switzerland) 20200625 12

In the light of the increasing occurrence of antifungal resistance, there is an urgent need to search for new therapeutic strategies to overcome this phenomenon. One of the applied approaches is the synthesis of small-molecule compounds showing antifungal properties. Here we present a continuation of the research on the recently discovered anti-Candida albicans agent 4-AN. Using next generation sequencing and transcriptional analysis, we revealed that the treatment of C. albicans w ...[more]

PMID: 32630522

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Project description:Candida albicans yeast cells are found in the intestine of most humans, yet this opportunist can invade host tissues and cause life-threatening infections in susceptible individuals. To better understand the host factors that underlie susceptibility to candidiasis, we developed a new model to study antifungal innate immunity. We demonstrate that the yeast form of C. albicans establishes an intestinal infection in Caenorhabditis elegans, whereas heat-killed yeast are avirulent. Genome-wide, transcription-profiling analysis of C. elegans infected with C. albicans yeast showed that exposure to C. albicans stimulated a rapid host response involving 313 genes (124 upregulated and 189 downregulated, ~1.6% of the genome) many of which encode antimicrobial, secreted or detoxification proteins. Interestingly, the host genes affected by C. albicans exposure overlapped only to a small extent with the distinct transcriptional responses to the pathogenic bacteria Pseudomonas aeruginosa or Staphylococcus aureus, indicating that there is a high degree of immune specificity toward different bacterial species and C. albicans. Furthermore, genes induced by P. aeruginosa and S. aureus were strongly over-represented among the genes downregulated during C. albicans infection, suggesting that in response to fungal pathogens, nematodes selectively repress the transcription of antibacterial immune effectors. A similar phenomenon is well known in the plant immune response, but has not been described previously in metazoans. Finally, 56% of the genes induced by live C. albicans were also upregulated by heat-killed yeast. These data suggest that a large part of the transcriptional response to C. albicans is mediated through "pattern recognition," an ancient immune surveillance mechanism able to detect conserved microbial molecules (so-called pathogen-associated molecular patterns or PAMPs). This study provides new information on the evolution and regulation of the innate immune response to divergent pathogens and demonstrates that nematodes selectively mount specific antifungal defenses at the expense of antibacterial responses.

Project description:Candida albicans, a ubiquitous opportunistic fungal pathogen, plays a pivotal role in human health and disease. As a commensal organism, it normally resides harmlessly within the human microbiota. However, under certain conditions, C. albicans can transition into a pathogenic state, leading to various infections collectively known as candidiasis. With the increasing prevalence of immunocompromised individuals and the widespread use of invasive medical procedures, candidiasis has become a significant public health concern. The emergence of drug-resistant strains further complicates treatment options, highlighting the urgent need for alternative therapeutic strategies. Antifungal peptides (AFPs) have gained considerable attention as potential candidates for combating Candida spp. infections. These naturally occurring peptides possess broad-spectrum antimicrobial activity, including specific efficacy against C. albicans. AFPs exhibit several advantageous properties, such as rapid killing kinetics, low propensity for resistance development, and diverse mechanisms of action, making them promising alternatives to conventional antifungal agents. In recent years, extensive research has focused on discovering and developing novel AFPs with improved efficacy and selectivity against Candida species. Advances in biotechnology and synthetic peptide design have enabled the modification and optimization of natural peptides, enhancing their stability, bioavailability, and therapeutic potential. Nevertheless, several challenges must be addressed before AFPs can be widely implemented in clinical practice. These include optimizing peptide stability, enhancing delivery methods, overcoming potential toxicity concerns, and conducting comprehensive preclinical and clinical studies. This commentary presents a short overview of candidemia and AFP; articles and reviews published in the last 10 years were searched on The National Library of Medicine (National Center for Biotechnology Information-NIH-PubMed). The terms used were C. albicans infections, antimicrobial peptides, antifungal peptides, antifungal peptides mechanisms of action, candidemia treatments and guidelines, synthetic peptides and their challenges, and antimicrobial peptides in clinical trials as the main ones. Older publications were cited if they brought some relevant concept or helped to bring a perspective into our narrative. Articles older than 20 years and those that appeared in PubMed but did not match our goal to bring updated information about using antifungal peptides as an alternative to C. albicans infections were not considered.

Project description:Magnolol, a lignin compound extracted from Magnolia officinalis Cortex, has been found to have prominent antifungal effects against Candida albicans. However, the specific mechanism still remains unclear. Therefore, this study aimed to further explore the inhibition mechanism of magnolol against Candida albicans virulence factors and the related signaling pathways. By an XTT reduction assay, a hyphal formation assay, confocal laser scanning microscopy, transmission electron microscopy, a calcofluor white staining assay, and a cell wall β-glucan quantitative detection assay, we evaluated the inhibitory effects of magnolol against the adhesion, hyphal formation, biofilm viability, biofilm spatial structure, and cell wall ultrastructure of Candida albicans. Moreover, by RNA sequencing and qRT-PCR, we confirmed the effects of magnolol in inhibiting the gene expression of Candida albicans virulence factors and the related signaling pathways. The results revealed that the adhesion and hyphal formation of Candida albicans were inhibited significantly by magnolol. The viability and spatial structures of Candida albicans biofilms were further weakened. Candida albicans ultrastructure showed partial thinning of cell walls and even rupture, with cytoplasmic leakage. The cell wall intergrity and β-glucan content were also radically reduced. Moreover, magnolol caused significant inhibition of the expression of Candida albicans adhesion, invasion, hyphal formation, biofilm formation, β-1,3-glucan synthesis, and hydrolase secretion-related genes, including ALS1, ALS3, EFG1, EAP1, FKS1, FKS2, PLB2, and SAP2. Furthermore, the PKC pathway-related genes (RHO1, PKC1, BCK1, MKK2, MKC1) and Cek1 pathway-related genes (CDC42, CST20, STE11, HST7, CEK1) were also significantly downregulated, indicating that the inhibition of magnolol against Candida albicans virulence factors might be related to PKC and Cek1 MAPK signaling pathways. In conclusion, the findings of this study confirmed the inhibition mechanism of magnolol against Candida albicans virulence factors, which might be related to PKC and Cek1 MAPK pathways, thus laying the theoretical foundation for its clinical antifungal applications.

Dataset Information

Antifungal Agent 4-AN Changes the Genome-Wide Expression Profile, Downregulates Virulence-Associated Genes and Induces Necrosis in Candida albicans Cells.

Publications

Antifungal Agent 4-AN Changes the Genome-Wide Expression Profile, Downregulates Virulence-Associated Genes and Induces Necrosis in <i>Candida albicans</i> Cells.

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