an-ex-vivo-assay-to-study-candida-albicans-hyphal-morphogenesis

An Ex vivo Assay to Study <em>Candida albicans</em> Hyphal Morphogenesis in the Gastrointestinal Tract

Candida albicans hyphal morphogenesis in the gastrointestinal (GI) tract is tightly controlled by various environmental signals, and plays an important ...

Midwestern University

Candida albicans is one of the most common causes of fungal infections in humans with a significant mortality rate. However, the factors involved in C. albicans gastrointestinal (GI) colonization remain unclear. We hypothesize that secondary bile acids have direct antifungal activity against C. albicans and may play a critical role in maintaining GI colonization resistance against C. albicans. In this study, we investigated the effect of secondary bile acids including lithocholic acid (LCA) and deoxycholic acid (DCA) on C. albicans growth and morphogenesis. Results indicate that LCA and DCA at in vivo cecal micelle concentrations inhibit C. albicans growth in vitro. Interestingly, LCA and DCA also significantly inhibited the germ tube, hyphae and biofilm formation in C. albicans. In addition, pre-treatment of C. albicans with LCA and DCA significantly reduced the percentage of C. albicans cells attached to a colon cancer cell line. Collectively, our results demonstrate that secondary bile acids play an important role in controlling the growth and morphological switching of C. albicans. Results from this study demonstrate that secondary bile acid possess direct antifungal activity against C. albicans, explaining a potential mechanism for gastrointestinal colonization resistance against C. albicans.

Secondary bile acids inhibit Candida albicans growth and morphogenesis.

A series of spirooxindolopyrrolidine fused -styrylpiperidone heterocyclic hybrids has been synthesized in excellent yield via a domino multicomponent protocol that involves one-pot three component 1,3-dipolar cycloaddition and concomitant enamine reactions performed in an inexpensive ionic liquid, namely 1-butyl-3-methylimidazolium bromide ([bmim]Br). Compounds thus synthesized were evaluated for their cytotoxicity against U-937 tumor cells. Interestingly; compounds  and  exhibited a better cytotoxicity than the anticancer drug bleomycin. In addition; the effect of the synthesized compounds on the nuclear morphology of U937 FaDu cells revealed that treatment with compounds ⁻ led to their apoptotic cell death.

Multicomponent Domino Synthesis, Anticancer Activity and Molecular Modeling Simulation of Complex Dispirooxindolopyrrolidines.

Candida albicans is a fungal pathogen that poses a significant public health risk due to high incidence and mortality rates among immunocompromised patients. Candida albicans infections begin with successful gastrointestinal (GI) colonization; however, the mechanisms behind this colonization remain to be elucidated. In this study, we investigated the role of taurocholic acid (TCA) on growth and GI colonization of C. albicans. Our results indicate that cefoperazone-treated mice susceptible to C. albicans infection had significantly increased levels of TCA in the gut contents. In addition, an increase in TCA levels directly correlates with higher C. albicans load in the fecal and gut contents of antibiotic-treated infected mice. Using in vitro assays, we also demonstrated that TCA enhances the growth of C. albicans and its ability to develop filamentous hyphae. Furthermore, TCA significantly increased the ability of C. albicans to attach to mammalian cells. These results demonstrate that antibiotic treatment alters TCA levels in the gut and potentially enhances GI colonization of C. albicans.

Antibiotic-induced alterations in taurocholic acid levels promote gastrointestinal colonization of Candida albicans.

Fungal infections caused by Candida and Cryptococcus are particularly dangerous for immunocompromised individuals. In this study, we identified that benzimidazole fused pyrrolo[3,4-b]quinoline compounds have potent antifungal activity against several clinical isolates of pathogenic fungal strains. Specifically, the compound 6a did not show cytotoxicity against mammalian cells at a concentration that inhibits the growth of fungal strains. In addition, the compound 6a also significantly reduced the metabolic activity of fungal cells in the Candida albicans biofilms. Collectively, our results indicate that benzimidazole fused quinoline compounds have a potential to develop as an antifungal agents.

Benzimidazole tethered pyrrolo[3,4-b]quinoline with broad-spectrum activity against fungal pathogens.

Candida albicans is the fourth most common cause of systemic nosocomial infections, posing a significant risk in immunocompromised individuals. As the majority of systemic C. albicans infections stem from endogenous gastrointestinal (GI) colonization, understanding the mechanisms associated with GI colonization is essential in the development of novel methods to prevent C. albicans-related mortality. In this study, we investigated the role of microbial-derived short-chain fatty acids (SCFAs) including acetate, butyrate, and propionate on growth, morphogenesis, and GI colonization of C. albicans. Our results indicate that cefoperazone-treated mice susceptible to C. albicans infection had significantly decreased levels of SCFAs in the cecal contents that correlate with a higher fungal load in the feces. Further, using in vivo concentration of SCFAs, we demonstrated that SCFAs inhibit the growth, germ tube, hyphae and biofilm development of C. albicans in vitro. Collectively, results from this study suggest that antibiotic-induced decreases in the levels of SCFAs in the cecum enhances the growth and GI colonization of C. albicans.

Antibiotic-induced decreases in the levels of microbial-derived short-chain fatty acids correlate with increased gastrointestinal colonization of Candida albicans.

Invasive fungal infections are one of the leading causes of nosocomial bloodstream infections with a limited treatment option. A series of derivatized spirooxindolo-pyrrolidine tethered indole and imidazole heterocyclic hybrids have been synthesized, and their antifungal activity against fungal strains were determined. Here we characterize the antifungal activity of a specific spirooxindolo-pyrrolidine hybrid, dubbed compound 9c, a spirooxindolo-pyrrolidine tethered imidazole synthesized with a 2-chloro and trifluoromethoxy substituent. The compound 9c exhibited no cytotoxicity against mammalian cell line at concentrations that inhibited fungal strains. Compound 9c also significantly inhibited the fungal hyphae and biofilm formation. Our results indicate that spirooxindolo-pyrrolidine heterocyclic hybrids potentially represent a broad class of chemical agents with promising antifungal potential.

Broad-spectrum antifungal activity of spirooxindolo-pyrrolidine tethered indole/imidazole hybrid heterocycles against fungal pathogens.

Antibiotic-induced alterations in the gut ecosystem increases the susceptibility to Candida albicans, yet the mechanisms involved remains poorly understood. Here we show that mice treated with the broad-spectrum antibiotic cefoperazone promoted the growth, morphogenesis and gastrointestinal (GI) colonization of C. albicans. Using metabolomics, we revealed that the cecal metabolic environment of the mice treated with cefoperazone showed a significant alteration in intestinal metabolites. Levels of carbohydrates, sugar alcohols and primary bile acids increased, whereas carboxylic acids and secondary bile acids decreased in antibiotic treated mice susceptible to C. albicans. Furthermore, using in-vitro assays, we confirmed that carbohydrates, sugar alcohols and primary bile acids promote, whereas carboxylic acids and secondary bile acids inhibit the growth and morphogenesis of C. albicans. In addition, in this study we report changes in the levels of gut metabolites correlated with shifts in the gut microbiota. Taken together, our in-vivo and in-vitro results indicate that cefoperazone-induced metabolome and microbiome alterations favor the growth and morphogenesis of C. albicans, and potentially play an important role in the GI colonization of C. albicans.

Antibiotic-induced gut metabolome and microbiome alterations increase the susceptibility to Candida albicans colonization in the gastrointestinal tract.

Candida albicans is a multimorphic commensal organism and opportunistic fungal pathogen in humans. A morphological switch between unicellular budding yeast and multicellular filamentous hyphal growth forms plays a vital role in the virulence of C. albicans, and this transition is regulated in response to a range of environmental cues that are encountered in distinct host niches. Many unique transcription factors contribute to the transcriptional regulatory network that integrates these distinct environmental cues and determines which phenotypic state will be expressed. These hyphal morphogenesis regulators have been extensively investigated, and represent an increasingly important focus of study, due to their central role in controlling a key C. albicans virulence attribute. This review provides a succinct summary of the transcriptional regulatory factors and environmental signals that control hyphal morphogenesis in C. albicans.

Transcriptional control of hyphal morphogenesis in Candida albicans.

Invasive fungal infections along with rising incidence of resistance to antifungal drugs pose increasing threat to immunocompromised individuals, including cancer patients. In this study, we examined the antifungal activity of dispiropyrrolidine tethered piperidone heterocyclic hybrids. Results indicate that compounds 5a and 6i have demonstrated a potent antifungal effect on multiple fungal strains, including Candida albicans, without exhibiting cytotoxicity to mammalian cells. Furthermore, these two compounds exhibited significant inhibition on Candida albicans hyphae and biofilm development that surpasses the FDA-approved antifungal drug currently used for treatment. Taken together, our results suggest that 5a and 6i are promising candidates for development into new antifungal drugs.

Dispiropyrrolidine tethered piperidone heterocyclic hybrids with broad-spectrum antifungal activity against Candida albicans and Cryptococcus neoformans.

Article	Year
Secondary bile acids inhibit Candida albicans growth and morphogenesis. Pathogens and disease\| PubMed ID: 29648597	2018
Multicomponent Domino Synthesis, Anticancer Activity and Molecular Modeling Simulation of Complex Dispirooxindolopyrrolidines. Molecules (Basel, Switzerland)\| PubMed ID: 29734741	2018
Antibiotic-induced alterations in taurocholic acid levels promote gastrointestinal colonization of Candida albicans. FEMS microbiology letters\| PubMed ID: 30137306	2018
Benzimidazole tethered pyrrolo[3,4-b]quinoline with broad-spectrum activity against fungal pathogens. Bioorganic & medicinal chemistry letters\| PubMed ID: 30655213	2019
Antibiotic-induced decreases in the levels of microbial-derived short-chain fatty acids correlate with increased gastrointestinal colonization of Candida albicans. Scientific reports\| PubMed ID: 31222159	2019
Broad-spectrum antifungal activity of spirooxindolo-pyrrolidine tethered indole/imidazole hybrid heterocycles against fungal pathogens. Bioorganic & medicinal chemistry letters\| PubMed ID: 31320146	2019
Antibiotic-induced gut metabolome and microbiome alterations increase the susceptibility to Candida albicans colonization in the gastrointestinal tract. FEMS microbiology ecology\| PubMed ID: 31769789	2020
Transcriptional control of hyphal morphogenesis in Candida albicans. FEMS yeast research\| PubMed ID: 31981355	2020
Dispiropyrrolidine tethered piperidone heterocyclic hybrids with broad-spectrum antifungal activity against Candida albicans and Cryptococcus neoformans. Bioorganic chemistry\| PubMed ID: 32361055	2020

Shankar Thangamani

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