High-Throughput Chemical Screen Identifies a 2,5-Disubstituted Pyridine as an Inhibitor of Candida albicans Erg11

Bois, Antonia C. Du; Xue, Alice; Pham, Chester; Revie, Nicole M.; Meyer, Kirsten J.; Yashiroda, Yoko; Boone, Charles; Nodwell, Justin R.; Stogios, P.J.; Savchenko, Alexei; Robbins, Nicole; Iyer, Kali R.; Cowen, Leah E.

doi:10.1128/msphere.00075-22

Cited by 4 publications

(3 citation statements)

References 23 publications

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“…The pleiotropic drug resistance transporter (PDR) belonging to the ABC transporters was found to be tightly associated with drug resistance. In Mucor circinelloides, out of the eight pdr genes, pdr1 and pdr2 was found to be involved in the resistance towards isavuconzaole, ravuconazole, and posaconazole 2,5-disubstituted pyridine compound CpdLC-6888 was found to inhibit Erg 11 similar to conventional azole drugs [55].…”

Section: Mechanism Antifungal Drug Resistancementioning

confidence: 96%

“…As most azole drugs exhibit their activity by targeting Erg11, by mining the existing repository of chemical compounds, new compounds targeting Erg 11 are explored to combat antifungal resistance. A 2,5-disubstituted pyridine compound CpdLC-6888 was found to inhibit Erg 11 similar to conventional azole drugs [ 55 ].…”

Section: Mechanism Antifungal Drug Resistancementioning

confidence: 99%

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Molecular Mechanisms of Antifungal Resistance in Mucormycosis

Ganesan

Ganapathy

Sekaran

et al. 2022

BioMed Research International

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Mucormycosis is one among the life-threatening fungal infections with high morbidity and mortality. It is an uncommon and rare infection targeting people with altered immunity. This lethal infection induced by fungi belonging to the Mucorales family is very progressive in nature. The incidence has increased in recent decades owing to the rise in immunocompromised patients. Disease management involves a multimodal strategy including early administration of drugs and surgical removal of infected tissues. Among the antifungals, azoles and amphotericin B remain the gold standard drugs of choice for initial treatment. The order Mucorales are developing a high level of resistance to the available systemic antifungal drugs, and the efficacy still remains below par. Deciphering the molecular mechanisms behind the antifungal resistance in Mucormycosis would add vital information to our available antifungal armamentarium and design novel therapies. Therefore, in this review, we have discussed the mechanisms behind Mucormycosis antifungal resistance. Moreover, this review also highlights the basic mechanisms of action of antifungal drugs and the resistance landscape which is expected to augment future treatment strategies.

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Section: Mechanism Antifungal Drug Resistancementioning

confidence: 96%

Section: Mechanism Antifungal Drug Resistancementioning

confidence: 99%

Molecular Mechanisms of Antifungal Resistance in Mucormycosis

Ganesan

Ganapathy

Sekaran

et al. 2022

BioMed Research International

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“…Analysis of individual genes showed that 12 ergosterol metabolism genes were significantly up-regulated in Esc7 in ethanol compared to SC5314 in ethanol (figure 2B). Importantly, one of these 12 genes was ERG11 which is one of the rate-limiting steps of ergosterol biosynthesis and the target of azole antifungals [18,19]. Previous work with Saccharomyces cerevisiae showed that ethanol impacts ergosterol production and that increased ergosterol production was correlated with increased ethanol tolerance [20][21][22][23], suggesting that the observed up-regulation of ERG genes contributes to ethanol tolerance of Esc7.…”

Section: Altered Gene Expression In Esc Strainsmentioning

confidence: 99%

Selection of Ethanol Tolerant Strains ofCandida albicansby Repeated Ethanol Exposure Results in Strains with Reduced Susceptibility to Fluconazole

Day,

Kumamoto

2023

Preprint

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Candida albicans is a commensal yeast that has important impacts on host metabolism and immune function, and can establish life-threatening infections in immunocompromised individuals. Previously, C. albicans colonization has been shown to contribute to the progression and severity of alcoholic liver disease. However, relatively little is known about how C. albicans responds to changing environmental conditions in the GI tract of individuals with alcohol use disorder, namely repeated exposure to ethanol. In this study, we repeatedly exposed C. albicans to high concentrations (10% vol/vol) of ethanol—a concentration that can be observed in the upper GI tract of humans following consumption of alcohol. Following this repeated exposure protocol, ethanol small colony (Esc) variants of C. albicans isolated from these populations exhibited increased ethanol tolerance, altered transcriptional responses to ethanol, and cross-resistance/tolerance to the frontline antifungal fluconazole. These Esc strains exhibited chromosomal copy number variations and carried polymorphisms in genes previously associated with the acquisition of fluconazole resistance during human infection. This study identifies a selective pressure that can result in evolution of fluconazole tolerance and resistance without previous exposure to the drug. Author Summary: Previous work has shown that Candida albicans, a common fungal component of the gastrointestinal (GI) microbiome, is found in high abundance in the alcoholic GI tract. However, it was unknown how repeated ethanol exposure, similar to what C. albicans would be exposed to in the upper GI tract of individuals with alcohol use disorder, would affect the yeast. In this work, we show that repeated ethanol exposure selects for C. albicans strains with altered transcriptional responses to ethanol, increased ethanol tolerance, and cross-resistance/tolerance to the common frontline antifungal fluconazole. This work shows that ethanol exposure can promote evolution of C. albicans to antifungal resistance without previous exposure to the antifungal drug. These findings could be relevant to C. albicans in the upper GI tract in individuals with alcohol use disorder and further studies could reveal optimized antifungal regimens for C. albicans infections in these patients.

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Going fishing: how to get what you want from a fungal genetic screen

O'Meara

2024

mSphere

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Five years ago, as I was starting my lab, I wrote about two functional genomic screens in fungi that had inspired me (mSphere 4:e00299-19, https://doi.org/10.1128/mSphere.00299-19 ). Now, I want to discuss some of the principles and questions that I ask myself and my students as we embark on our own screens. A good screen, whether it is a genetic or chemical screen, can be the starting point for new discovery and an excellent basis for the beginning of a scientific research project. However, screens are often criticized for being “fishing expeditions.” To stretch this metaphor to the extreme, this is because people are worried that we do not know how to fish, that we will come home without any fish, bring home the wrong fish, or not know what to do with a fish if we caught it. How you set up the screen and analyze the results determines whether the screen will be useful. In this mini-review, and in the spirit of teaching a scientist to fish, I will discuss recent excellent fungal genetic and chemical screens that illustrate some of the key aspects of a successful screen.

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High-Throughput Chemical Screen Identifies a 2,5-Disubstituted Pyridine as an Inhibitor of Candida albicans Erg11

Cited by 4 publications

References 23 publications

Molecular Mechanisms of Antifungal Resistance in Mucormycosis

Molecular Mechanisms of Antifungal Resistance in Mucormycosis

Selection of Ethanol Tolerant Strains ofCandida albicansby Repeated Ethanol Exposure Results in Strains with Reduced Susceptibility to Fluconazole

Going fishing: how to get what you want from a fungal genetic screen

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