SAGA/ADA Complex Subunit Ada2 Is Required for Cap1- but Not Mrr1-Mediated Upregulation of the Candida albicans Multidrug Efflux Pump
            <i>MDR1</i>

Ramı́rez-Zavala, Bernardo; Mogavero, Selene; Schöller, Eva; Sasse, Christoph; Rogers, P. David; Morschhäuser, Joachim

doi:10.1128/aac.03065-14

Cited by 24 publications

(22 citation statements)

References 30 publications

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“…For example, the SAGA/Ada complex has been shown to be important for upregulation of MDR1 expression in C. albicans (13). The SAGA complex and nuclear acetyl-CoA synthetase 2 are required for histone acetylation in yeast (37). We have shown that AR-12 blocks histone acetylation in C. albicans (10).…”

Section: Resultsmentioning

confidence: 75%

The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis

Koselny

Green

DiDone

et al. 2016

Antimicrob Agents Chemother

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gOnly one new class of antifungal drugs has been introduced into clinical practice in the last 30 years, and thus the identification of small molecules with novel mechanisms of action is an important goal of current anti-infective research. Here, we describe the characterization of the spectrum of in vitro activity and in vivo activity of AR-12, a celecoxib derivative which has been tested in a phase I clinical trial as an anticancer agent. AR-12 inhibits fungal acetyl coenzyme A (acetyl-CoA) synthetase in vitro and is fungicidal at concentrations similar to those achieved in human plasma. AR-12 has a broad spectrum of activity, including activity against yeasts (e.g., Candida albicans, non-albicans Candida spp., Cryptococcus neoformans), molds (e.g., Fusarium, Mucor), and dimorphic fungi (Blastomyces, Histoplasma, and Coccidioides) with MICs of 2 to 4 g/ml. AR-12 is also active against azole-and echinocandin-resistant Candida isolates, and subinhibitory AR-12 concentrations increase the susceptibility of fluconazole-and echinocandin-resistant Candida isolates. Finally, AR-12 also increases the activity of fluconazole in a murine model of cryptococcosis. Taken together, these data indicate that AR-12 represents a promising class of small molecules with broad-spectrum antifungal activity.T he treatment of life-threatening invasive fungal infections (IFIs) remains a significant challenge to modern medicine (1, 2). Two primary factors contribute to the difficult nature of IFI therapy. First, most IFIs affect people with compromised immune function, and therefore, IFI patients are more reliant on the efficacy of the antifungal drug than immunocompetent patients. Second, the development of effective antifungal drugs is difficult, because many fundamental biological processes are highly conserved between fungi and humans (3). Consequently, identifying molecules that kill the pathogen and spare the host is very challenging. Currently, only three primary classes of antifungal drugs are in clinical use: (i) azole ergosterol biosynthesis inhibitors (e.g., fluconazole [FLU]), (ii) polyene ergosterol binding agents (e.g., amphotericin B), and (iii) echinocandin 1,3-␤-D-glucan synthase inhibitors (e.g., caspofungin). The number of antifungal drugs pales in comparison to the number of distinct classes of antimicrobial agents, and, in fact, there are currently more classes of antiretroviral agents available for the treatment of HIV/AIDS than classes of antifungal drugs (2).The pace of antifungal drug development has been extremely slow. For example, the most recent addition to the antifungal pharmacopeia, the echinocandins, was discovered in the early 1970s and introduced into clinical practice in the early 2000s (3). Furthermore, no new drugs for the treatment of cryptococcal meningitis, one of the most important causes of infectious disease-related deaths in HIV/AIDS patients (4), have been introduced into clinical practice in more than 20 years. In fact, the current gold standard therapy is based on drugs (amphotericin B an...

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Section: Resultsmentioning

confidence: 75%

The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis

Koselny

Green

DiDone

et al. 2016

Antimicrob Agents Chemother

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“…The impact of the Swi/Snf complex on fluconazole resistance in MRR1 GOF strains is among the most severe observed among the coactivators studied to date for C. albicans zinc cluster transcription factor GOF azole resistance mutants (23,48). The deletion of snf2 reduced the fluconazole MIC in the MRR1 GOF strains to levels comparable to those of azole-sensitive MRR1 WT strains.…”

Section: Discussionmentioning

confidence: 99%

Candida albicans Swi/Snf and Mediator Complexes Differentially Regulate Mrr1-Induced MDR1 Expression and Fluconazole Resistance

Liu

Myers

2017

Antimicrob Agents Chemother

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Long-term azole treatment of patients with chronic infections can lead to drug resistance. Gain-of-function (GOF) mutations in the transcription factor Mrr1 and the consequent transcriptional activation of, a drug efflux coding gene, is a common pathway by which this human fungal pathogen acquires fluconazole resistance. This work elucidates the previously unknown downstream transcription mechanisms utilized by hyperactive Mrr1. We identified the Swi/Snf chromatin remodeling complex as a key coactivator for Mrr1, which is required to maintain basal and induced open chromatin, and Mrr1 occupancy, at the promoter. Deletion of, the catalytic subunit of Swi/Snf, largely abrogates the increases in expression and fluconazole MIC observed in mutant strains. Mediator positively and negatively regulates key Mrr1 target promoters. Deletion of the Mediator tail module subunit reduces, but does not eliminate, the increased expression and fluconazole MIC conferred by mutations. Eliminating the kinase activity of the Mediator Ssn3 subunit suppresses the decreased expression and fluconazole MIC of the null mutation in strains. Ssn3 deletion also suppresses promoter histone displacement defects in null mutants. The combination of this work with studies on other hyperactive zinc cluster transcription factors that confer azole resistance in fungal pathogens reveals a complex picture where the induction of drug efflux pump expression requires the coordination of multiple coactivators. The observed variations in transcription factor and target promoter dependence of this process may make the search for azole sensitivity-restoring small molecules more complicated.

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“…Nantel's group also found that Ada2-depleted C. albicans cannot express some Cap1-regulated genes under the oxidative stress condition, and that Ada2's recruitment to the promoter of Cap1-regulated genes is Cap1-dependent [19]. The way by which Ada2 regulates gene expression in a Cap1-dependent manner is consistent with the regulatory mechanism of the drug-resistant genes by Ada2 and Cap1 in C. albicans [19,42]. Although the mechanisms of how Ada2 regulates the oxidative stress-responsive genes remain to be elucidated in C. albicans, the HAT module of the SAGA complex containing Ada2 regulates some Cap1regulated genes by interacting with Cap1 transcription factor and by acetylating these genes' promoters in C. albicans ( Fig.…”

Section: Hat Module Of the Saga Complex: Its Positive Regulation Of Omentioning

confidence: 72%

Epigenetic Control of Oxidative Stresses by Histone Acetyltransferases in Candida albicans

Kim

Park

Lee

2018

Journal of Microbiology and Biotechnology

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is a major pathogenic fungus in humans, and meets at first the innate immune cells, such as macrophages, in its host. One important strategy of the host cell to kill is to produce reactive oxygen species (ROS) by the macrophages. In response to ROS produced by the macrophages, operates its defense mechanisms against them by expressing its oxidative stress response genes. Although there have been many research studies explaining the specific transcription factors and the expression of the oxidative stress genes in , the regulation of the oxidative stress genes by chromatin structure is little known. Epigenetic regulation by the chromatin structure is very important for the regulation of eukaryotic gene expression, including the chromatin structure dynamics by histone modifications. Among various histone modifications, histone acetylation is reported for its direct relationship to the regulation of gene expression. Recent studies reported that histone acetyltransferases regulate genes to respond to the oxidative stress in. In this review, we introduce all histone acetyltransferases that contains and some papers that explain how histone acetyltransferases participate in the oxidative stress response in.

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SAGA/ADA Complex Subunit Ada2 Is Required for Cap1- but Not Mrr1-Mediated Upregulation of the Candida albicans Multidrug Efflux Pump MDR1

Cited by 24 publications

References 30 publications

The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis

The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis

Candida albicans Swi/Snf and Mediator Complexes Differentially Regulate Mrr1-Induced MDR1 Expression and Fluconazole Resistance

Epigenetic Control of Oxidative Stresses by Histone Acetyltransferases in Candida albicans

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