Inhibiting fungal multidrug resistance by disrupting an activator–Mediator interaction

Nishikawa, Joy L.; Boeszoermenyi, Andras; Vale-Silva, Luís A.; Torelli, Riccardo; Posteraro, Brunella; Sohn, Yoojin; Ji, Fei; Gelev, Vladimir; Sanglard, Dominique; Sadreyev, Ruslan I.; Mukherjee, Goutam; Jayaram, B.; Buhrlage, Sara J.; Gray, Nathanael S.; Wagner, Gerhard; Näär, Anders M.; Arthanari, Haribabu

doi:10.1038/nature16963

Cited by 120 publications

(101 citation statements)

References 25 publications

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“…A comparative knowledge of these different mechanisms is important, as therapeutic intervention downstream of zinc cluster transcription factor hyperactivation is considered to reduce drug resistance. Work in C. glabrata suggests small molecules that interfere with interactions between transcription factors, which drive efflux pump expression, and Mediator could be effective at restoring azole sensitivity to this pathogen with an intrinsically high resistance to fluconazole (6). If such a strategy were to be undertaken in C. albicans, the differential coactivator dependence of Mrr1 GOF and Tac1 GOF efflux pump gene activation we have identified here indicates that the small molecules have to be selected for the specific transcription factor/coactivator pair involved.…”

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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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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“…C. glabrata readily develops cross-resistance to azoles, including fluconazole, itraconazole, voriconazole and posaconazole, which is often associated with upregulation of ATP-binding cassette (ABC) transporters, such as CDR1 and SNQ2 , that effectively pump the drugs out of the yeast cell (Sanglard et al, 1999, 2001; Izumikawa et al, 2003; Torelli et al, 2008). Upregulation of these drug efflux pumps is usually accompanied by a gain-of-function mutation in the transcription factor PDR1 (Vermitsky and Edlind, 2004; Tsai et al, 2006; Vermitsky et al, 2006), prompting the recent development of a novel inhibitor that interferes with Pdr1 binding to the Mediator complex preventing transcription initiation (Nishikawa et al, 2016). Specific pdr1 mutations in C. glabrata can also lead to a gain of fitness through enhanced adhesion and virulence (Ferrari et al, 2011; Vale-Silva et al, 2013, 2016).…”

Section: Epidemiology Of Fungal Infections and Treatment Optionsmentioning

confidence: 99%

Genetic Drivers of Multidrug Resistance in Candida glabrata

et al. 2016

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Both the incidence of invasive fungal infections and rates of multidrug resistance associated with fungal pathogen Candida glabrata have increased in recent years. In this perspective, we will discuss the mechanisms underlying the capacity of C. glabrata to rapidly develop resistance to multiple drug classes, including triazoles and echinocandins. We will focus on the extensive genetic diversity among clinical isolates of C. glabrata, which likely enables this yeast to survive multiple stressors, such as immune pressure and antifungal exposure. In particular, over half of C. glabrata clinical strains collected from U.S. and non-U.S. sites have mutations in the DNA mismatch repair gene MSH2, leading to a mutator phenotype and increased frequencies of drug-resistant mutants in vitro. Furthermore, recent studies and data presented here document extensive chromosomal rearrangements among C. glabrata strains, resulting in a large number of distinct karyotypes within a single species. By analyzing clonal, serial isolates derived from individual patients treated with antifungal drugs, we were able to document chromosomal changes occurring in C. glabrata in vivo during the course of antifungal treatment. Interestingly, we also show that both MSH2 genotypes and chromosomal patterns cluster consistently into specific strain types, indicating that C. glabrata has a complex population structure where genomic variants arise, perhaps during the process of adaptation to environmental changes, and persist over time.

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“…4). In fact, a new antibiotic that inhibits the interaction between a mediator subunit with a transcriptional activator and that preferentially kills a pathogen fungus has recently been identified 53. A similar approach may be used to look for new inhibitors of TFIIH.…”

Section: Discussionmentioning

confidence: 99%

TFIIH: New Discoveries Regarding its Mechanisms and Impact on Cancer Treatment

Zurita¹,

Cruz‐Becerra²

2016

J. Cancer

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The deregulation of gene expression is a characteristic of cancer cells, and malignant cells require very high levels of transcription to maintain their cancerous phenotype and survive. Therefore, components of the basal transcription machinery may be considered as targets to preferentially kill cancerous cells. TFIIH is a multisubunit basal transcription factor that also functions in nucleotide excision repair. The recent discoveries of some small molecules that interfere with TFIIH and that preferentially kill cancer cells have increased researchers' interest to elucidate the complex mechanisms by which TFIIH operates. In this review, we summarize the knowledge generated during the 25 years of TFIIH research, highlighting the recent advances in TFIIH structural and mechanistic analyses that suggest the potential of TFIIH as a target for cancer treatment.

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Inhibiting fungal multidrug resistance by disrupting an activator–Mediator interaction

Cited by 120 publications

References 25 publications

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

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

Genetic Drivers of Multidrug Resistance in Candida glabrata

TFIIH: New Discoveries Regarding its Mechanisms and Impact on Cancer Treatment

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