Selective BET bromodomain inhibition as an antifungal therapeutic strategy

Mietton, Flore; Ferri, Elena; Champleboux, Morgane; Zala, Ninon; Maubon, Danièle; Zhou, Yingsheng; Harbut, M.; Spittler, Didier; Garnaud, Cécile; Courçon, Marie; Chauvel, Murielle; d’Enfert, Christophe; Kashemirov, B. A.; Hull, Mitchell V.; Cornet, Muriel; McKenna, Charles E.; Govin, Jérôme; Petosa, Carlo

doi:10.1038/ncomms15482

Cited by 41 publications

(59 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, in S. cerevisiae , ScBDF1 and ScBDF2 are each dispensable and yet dependent upon the presence of the other ( 55 ). The single gene CaBDF1 was found to be essential both in CaTn analysis (see Dataset 2A at https://doi.org/10.6084/m9.figshare.c.4251182 ) and in classical deletion studies ( 56 ). Indeed, 101 of these 252 genes are found in single-copy form in C. albicans and have paralogs in at least one of the two model yeasts ( 57 – 59 ) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Gene Essentiality Analyzed by In Vivo Transposon Mutagenesis and Machine Learning in a Stable Haploid Isolate of Candida albicans

Segal

Gritsenko

Levitan

et al. 2018

mBio

122

147

View full text Add to dashboard Cite

Comprehensive understanding of an organism requires that we understand the contributions of most, if not all, of its genes. Classical genetic approaches to this issue have involved systematic deletion of each gene in the genome, with comprehensive sets of mutants available only for very-well-studied model organisms. We took a different approach, harnessing the power of in vivo transposition coupled with deep sequencing to identify >500,000 different mutations, one per cell, in the prevalent human fungal pathogen Candida albicans and to map their positions across the genome. The transposition approach is efficient and less labor-intensive than classic approaches. Here, we describe the production and analysis (aided by machine learning) of a large collection of mutants and the comprehensive identification of 1,610 C. albicans genes that are essential for growth under standard laboratory conditions. Among these C. albicans essential genes, we identify those that are also essential in two distantly related model yeasts as well as those that are conserved in all four major human fungal pathogens and that are not conserved in the human genome. This list of genes with functions important for the survival of the pathogen provides a good starting point for the development of new antifungal drugs, which are greatly needed because of the emergence of fungal pathogens with elevated resistance and/or tolerance of the currently limited set of available antifungal drugs.

show abstract

Section: Resultsmentioning

confidence: 99%

Gene Essentiality Analyzed by In Vivo Transposon Mutagenesis and Machine Learning in a Stable Haploid Isolate of Candida albicans

Segal

Gritsenko

Levitan

et al. 2018

mBio

122

147

View full text Add to dashboard Cite

show abstract

“…80.000 chemically diverse compounds by a HTRF inhibition assay revealed GBB 133. [215] Compound 133 inhibits the CaBdf1 BD2 with high selectivity: HTRF and ITC assays Figure 5. Second Bromodomain (BD2) from Candida albicans Bdf1 binding to an GBB imidazopyridine (PDB 5N18).…”

Section: Structural Biologymentioning

confidence: 99%

“…Screening a library of ca. 80.000 chemically diverse compounds by a HTRF inhibition assay revealed GBB 133 . Compound 133 inhibits the Ca Bdf1 BD2 with high selectivity: HTRF and ITC assays yielded IC 50 and K d values of 1.1 and 2.1 µ m , respectively, whereas human Brd4 BD2 and Ca Bdf1 BD1 were only weakly inhibited (IC 50 ≥ 40 µ m ).…”

Section: Structural Biologymentioning

confidence: 99%

The Groebke‐Blackburn‐Bienaymé Reaction

2019

View full text Add to dashboard Cite

Imidazo[1,2‐a]pyridine is a well‐known scaffold in many marketed drugs, such as Zolpidem, Minodronic acid, Miroprofen and DS‐1 and it also serves as a broadly applied pharmacophore in drug discovery. The scaffold revoked a wave of interest when Groebke, Blackburn and Bienaymé reported independently a new three component reaction resulting in compounds with the imidazo[1,2‐a]‐heterocycles as a core structure. During the course of two decades the Groebke Blackburn Bienaymé (GBB‐3CR) reaction has emerged as a very important multicomponent reaction (MCR), resulting in over a hundred patents and a great number of publications in various fields of interest. Now two compounds derived from GBB‐3CR chemistry received FDA approval. To celebrate the first 20 years of GBB‐chemistry, we present an overview of the chemistry of the GBB‐3CR, including an analysis of each of the three starting material classes, solvents and catalysts. Additionally, a list of patents and their applications and a more in‐depth summary of the biological targets that were addressed, including structural biology analysis, is given.

show abstract

“…Our findings make the CaRSC attractive in this context. Despite the complex being conserved across the fungal pathogen and the human host, small molecule inhibitors selectively targeting distinct catalytic residues could serve as potent antifungal agents as demonstrated elsewhere [53]. Alternatively, targeting Candida-specific subunits (Nri1 and Nri2) of the complex presents yet another possibility to explore in the future.…”

Section: Plos Geneticsmentioning

confidence: 99%

The RSC (Remodels the Structure of Chromatin) complex of Candida albicans shows compositional divergence with distinct roles in regulating pathogenic traits

et al. 2020

View full text Add to dashboard Cite

Regulation of gene expression programs is crucial for the survival of microbial pathogens in host environments and for their ability to cause disease. Here we investigated the epigenetic regulator RSC (Remodels the Structure of Chromatin) in the most prevalent human fungal pathogen Candida albicans. Biochemical analysis showed that CaRSC comprises 13 subunits and contains two novel non-essential members, which we named Nri1 and Nri2 (Novel RSC Interactors) that are exclusive to the CTG clade of Saccharomycotina. Genetic analysis showed distinct essentiality of C. albicans RSC subunits compared to model fungal species suggesting functional and structural divergence of RSC functions in this fungal pathogen. Transcriptomic and proteomic profiling of a conditional mutant of the essential catalytic subunit gene STH1 demonstrated global roles of RSC in C. albicans biology, with the majority of growth-related processes affected, as well as mis-regulation of genes involved in morphotype switching, host-pathogen interaction and adaptive fitness. We further assessed the functions of non-essential CaRSC subunits, showing that the novel subunit Nri1 and the bromodomain subunit Rsc4 play roles in filamentation and stress responses; and also interacted at the genetic level to regulate cell viability. Consistent with these roles, Rsc4 is required for full virulence of C. albicans in the murine model of systemic infection. Taken together, our data builds the first comprehensive study of the composition and roles of RSC in C. albicans, showing both conserved and distinct features compared to model fungal systems. The study illuminates how C. albicans uses RSC-dependent transcriptional regulation to respond to environmental signals and drive survival fitness and virulence in mammals.

show abstract

Selective BET bromodomain inhibition as an antifungal therapeutic strategy

Cited by 41 publications

References 70 publications

Gene Essentiality Analyzed by In Vivo Transposon Mutagenesis and Machine Learning in a Stable Haploid Isolate of Candida albicans

Gene Essentiality Analyzed by In Vivo Transposon Mutagenesis and Machine Learning in a Stable Haploid Isolate of Candida albicans

The Groebke‐Blackburn‐Bienaymé Reaction

The RSC (Remodels the Structure of Chromatin) complex of Candida albicans shows compositional divergence with distinct roles in regulating pathogenic traits

Contact Info

Product

Resources

About