Hitting the Caspofungin Salvage Pathway of Human-Pathogenic Fungi with the Novel Lasso Peptide Humidimycin (MDN-0010)

Valiante, Vito; Monteiro, Maria Cândida; Martín, Jesús; Altwasser, Robert; Aouad, Noureddine El; González, Ignacio; Kniemeyer, Olaf; Mellado, Emilia; Palomo, Sara; Pedro, Nuria de; Pérez-Victoria, Ignacio; Tormo, José R.; Vicente, Francisca; Reyes, Fernando; Genilloud, Olga; Brakhage, Axel A.

doi:10.1128/aac.00683-15

Cited by 37 publications

(38 citation statements)

References 40 publications

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“…To exemplarily present the capabilities of GEO2RNAseq, we re-analysed the RNA-seq dataset GSE55663 Valiante et al (2015), which is freely available at GEO 4 , using only metadata provided within GSE55663. This dataset is based on RNA-seq results from of Aspergillus fumigatus treated with Caspofungin and Siamycin.…”

Section: Application and Example Resultsmentioning

confidence: 99%

GEO2RNAseq: An easy-to-use R pipeline for complete pre-processing of RNA-seq data

Seelbinder

Wolf

Priebe

et al. 2019

Preprint

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1In transcriptomics, the study of the total set of RNAs transcribed by the cell, RNA sequencing 2 (RNA-seq) has become the standard tool for analysing gene expression. The primary goal is 3 the detection of genes whose expression changes significantly between two or more conditions, 4 either for a single species or for two or more interacting species at the same time (dual RNA-seq, 5 triple RNA-seq and so forth). The analysis of RNA-seq can be simplified as many steps of the 6 data pre-processing can be standardised in a pipeline. 7 In this publication we present the "GEO2RNAseq" pipeline for complete, quick and concurrent 8 pre-processing of single, dual, and triple RNA-seq data. It covers all pre-processing steps 9 starting from raw sequencing data to the analysis of differentially expressed genes, including 10 various tables and figures to report intermediate and final results. Raw data may be provided 11 in FASTQ format or can be downloaded automatically from the Gene Expression Omnibus 12 repository. GEO2RNAseq strongly incorporates experimental as well as computational metadata. 13 GEO2RNAseq is implemented in R, lightweight, easy to install via Conda and easy to use, but still 14 very flexible through using modular programming and offering many extensions and alternative 15 workflows. 16 GEO2RNAseq is publicly available at https://anaconda.org/xentrics/r-geo2rnaseq 17 and https://bitbucket.org/thomas_wolf/geo2rnaseq/overview, including source 18 code, installation instruction, and comprehensive package documentation. 19 1 Seelbinder et al. GEO2RNAseqthe detection of genes whose expression changes significantly between two or more conditions, and the 25 function relationship of these genes. RNA sequencing (RNA-seq) offers a complete, fast, and cheap way 26 to perform transcriptomics of single organisms using next-generation-sequencing technologies (Mardis, 27 2008). However, species do not exist in isolation. In fact, interspecies interactions are a major part of 28 environmental adaptation. The special variant dual RNA-seq can be applied to analyse the transcriptome 29 of two interacting species at the same time by separating their RNA in silico (Schulze et al., 2016; Wolf 30 et al., 2018). The concept of dual RNA-seq can be further extended: triple RNA-seq allows investigating 31 the interaction of three organisms, e. g. a host and two competing pathogens. 32Both, the number of scientists applying RNA-seq and the number of published datasets have been growing 33 exponentially 1 (Deelen et al., 2014). However, the bottlenecks in transcriptomics are the small number 34 of experts able to pre-process and analyse RNA-seq data, and the small number of easy-to-use tools. A 35 number of pipelines were published in R to handle this issue, but none of them includes the complete set of 36 pre-processing steps and none exploits the available metadata fully. 37Extensive utilisation of metadata is highly important. Wet-lab metadata, e. g. temperature or pH, and 38 dry-lab metadata, e. ...

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Section: Application and Example Resultsmentioning

confidence: 99%

GEO2RNAseq: An easy-to-use R pipeline for complete pre-processing of RNA-seq data

Seelbinder

Wolf

Priebe

et al. 2019

Preprint

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“…For instance, psoriasin (also known as S100A7), a mammalian protein that is commonly found in psoriatic lesions, has antifungal activity, particularly against Trichophyton rubrum 54 . Other products such as humidimycin (also known as MDN-0010), a bacterial natural product, potentiate known antifungal agents by targeting an echinocandin salvage pathway 55 . Although nature can help to select antifungal compounds, we must then make them into drugs.…”

Section: Novel Pathways and Targetsmentioning

confidence: 99%

The antifungal pipeline: a reality check

Perfect

2017

Nat Rev Drug Discov

634

575

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Invasive fungal infections continue to appear in record numbers as the immunocompromised population of the world increases, owing partially to the increased number of individuals who are infected with HIV and partially to the successful treatment of serious underlying diseases. The effectiveness of current antifungal therapies — polyenes, flucytosine, azoles and echinocandins (as monotherapies or in combinations for prophylaxis, or as empiric, pre-emptive or specific therapies) — in the management of these infections has plateaued. Although these drugs are clinically useful, they have several limitations, such as off-target toxicity, and drug-resistant fungi are now emerging. New antifungals are therefore needed. In this Review, I discuss the robust and dynamic antifungal pipeline, including results from preclinical academic efforts through to pharmaceutical industry products, and describe the targets, strategies, compounds and potential outcomes.

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“…Another interesting aspect was the upregulation upon osmotic stress of several genes encoding for protein kinases related to calcium and TOR, such as calcium calmodulin (CmkD showed only a discrete increase. It has been proposed that increased concentrations of caspofungin promoted activation and cross-talk between the A. fumigatus MpkA and SakA pathways (Altwasser et al, 2015;Bruder Nascimento et al, 2016;Valiante et al, 2015b). Additionally, the existence of a salvage pathway, possibly dependent on MpkC and SakA, which would compensate the caspofungin stress response, has been proposed (Valiante et al, 2015b).…”

Section: Atfa Is Important For a Fumigatus Virulence In Both Gallementioning

confidence: 99%

Genome-wide transcriptome analysis ofAspergillus fumigatusexposed to osmotic stress reveals regulators of osmotic and cell wall stresses that are SakA^HOG1and MpkC dependent

Silva

Castro

Reis

et al. 2016

Cellular Microbiology

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Invasive aspergillosis is predominantly caused by Aspergillus fumigatus, and adaptations to stresses experienced within the human host are a prerequisite for the survival and virulence strategies of the pathogen. The central signal transduction pathway operating during hyperosmotic stress is the high osmolarity glycerol mitogen-activated protein kinase cascade. A. fumigatus MpkC and SakA, orthologues of the Saccharomyces cerevisiae Hog1p, constitute the primary regulator of the hyperosmotic stress response. We compared A. fumigatus wild-type transcriptional response to osmotic stress with the ΔmpkC, ΔsakA, and ΔmpkC ΔsakA strains. Our results strongly indicate that MpkC and SakA have independent and collaborative functions during the transcriptional response to transient osmotic stress. We have identified and characterized null mutants for four A. fumigatus basic leucine zipper proteins transcription factors. The atfA and atfB have comparable expression levels with the wild-type in ΔmpkC but are repressed in ΔsakA and ΔmpkC ΔsakA post-osmotic stress. The atfC and atfD have reduced expression levels in all mutants post-osmotic stress. The atfA-D null mutants displayed several phenotypes related to osmotic, oxidative, and cell wall stresses. The ΔatfA and ΔatfB were shown to be avirulent and to have attenuated virulence, respectively, in both Galleria mellonella and a neutropenic murine model of invasive pulmonary aspergillosis.

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Hitting the Caspofungin Salvage Pathway of Human-Pathogenic Fungi with the Novel Lasso Peptide Humidimycin (MDN-0010)

Cited by 37 publications

References 40 publications

GEO2RNAseq: An easy-to-use R pipeline for complete pre-processing of RNA-seq data

GEO2RNAseq: An easy-to-use R pipeline for complete pre-processing of RNA-seq data

The antifungal pipeline: a reality check

Genome-wide transcriptome analysis ofAspergillus fumigatusexposed to osmotic stress reveals regulators of osmotic and cell wall stresses that are SakA^HOG1and MpkC dependent

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Hitting the Caspofungin Salvage Pathway of Human-Pathogenic Fungi with the Novel Lasso Peptide Humidimycin (MDN-0010)

Cited by 37 publications

References 40 publications

GEO2RNAseq: An easy-to-use R pipeline for complete pre-processing of RNA-seq data

GEO2RNAseq: An easy-to-use R pipeline for complete pre-processing of RNA-seq data

The antifungal pipeline: a reality check

Genome-wide transcriptome analysis ofAspergillus fumigatusexposed to osmotic stress reveals regulators of osmotic and cell wall stresses that are SakAHOG1and MpkC dependent

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Genome-wide transcriptome analysis ofAspergillus fumigatusexposed to osmotic stress reveals regulators of osmotic and cell wall stresses that are SakA^HOG1and MpkC dependent