Exposure of Aspergillus fumigatus to caspofungin results in the release, and de novo biosynthesis, of gliotoxin

Eshwika, Ahmed; Kelly, Judy; Fallon, John P.; Kavanagh, Kevin

doi:10.3109/13693786.2012.688180

Cited by 5 publications

(3 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another interesting finding was the increased production of the secondary metabolite fumagillin upon exposure of A. fumigatus to caspofungin. So far, only the release of the secondary metabolite gliotoxin has been reported for cultures of A. fumigatus in the presence of caspofungin [ 56 ]. Fumagillin has anti-angiogenic activity [ 57 ] and induces cell death in erythrocytes [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Module-detection approaches for the integration of multilevel omics data highlight the comprehensive response of Aspergillus fumigatus to caspofungin

et al. 2018

View full text Add to dashboard Cite

BackgroundOmics data provide deep insights into overall biological processes of organisms. However, integration of data from different molecular levels such as transcriptomics and proteomics, still remains challenging. Analyzing lists of differentially abundant molecules from diverse molecular levels often results in a small overlap mainly due to different regulatory mechanisms, temporal scales, and/or inherent properties of measurement methods. Module-detecting algorithms identifying sets of closely related proteins from protein-protein interaction networks (PPINs) are promising approaches for a better data integration.ResultsHere, we made use of transcriptome, proteome and secretome data from the human pathogenic fungus Aspergillus fumigatus challenged with the antifungal drug caspofungin. Caspofungin targets the fungal cell wall which leads to a compensatory stress response. We analyzed the omics data using two different approaches: First, we applied a simple, classical approach by comparing lists of differentially expressed genes (DEGs), differentially synthesized proteins (DSyPs) and differentially secreted proteins (DSePs); second, we used a recently published module-detecting approach, ModuleDiscoverer, to identify regulatory modules from PPINs in conjunction with the experimental data. Our results demonstrate that regulatory modules show a notably higher overlap between the different molecular levels and time points than the classical approach. The additional structural information provided by regulatory modules allows for topological analyses. As a result, we detected a significant association of omics data with distinct biological processes such as regulation of kinase activity, transport mechanisms or amino acid metabolism. We also found a previously unreported increased production of the secondary metabolite fumagillin by A. fumigatus upon exposure to caspofungin. Furthermore, a topology-based analysis of potential key factors contributing to drug-caused side effects identified the highly conserved protein polyubiquitin as a central regulator. Interestingly, polyubiquitin UbiD neither belonged to the groups of DEGs, DSyPs nor DSePs but most likely strongly influenced their levels.ConclusionModule-detecting approaches support the effective integration of multilevel omics data and provide a deep insight into complex biological relationships connecting these levels. They facilitate the identification of potential key players in the organism’s stress response which cannot be detected by commonly used approaches comparing lists of differentially abundant molecules.Electronic supplementary materialThe online version of this article (10.1186/s12918-018-0620-8) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

Module-detection approaches for the integration of multilevel omics data highlight the comprehensive response of Aspergillus fumigatus to caspofungin

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The activation of the fumagillin cluster during experimental animal infections has been detected, contributing to the invasion and generation of cell damage [40]. Other authors have shown that, in contact with caspofungin, fumagillin [87] and gliotoxin [88] are overexpressed. This implies that the treatment with caspofungin could have adverse effects on host cells during infection.…”

Section: Regulation Of Fumagillin Clustermentioning

confidence: 99%

Fumagillin, a Mycotoxin of Aspergillus fumigatus: Biosynthesis, Biological Activities, Detection, and Applications

Guruceaga

Perez-Cuesta

Abad‐Diaz‐de‐Cerio

et al. 2019

Toxins

View full text Add to dashboard Cite

Fumagillin is a mycotoxin produced, above all, by the saprophytic filamentous fungus Aspergillus fumigatus. This mold is an opportunistic pathogen that can cause invasive aspergillosis, a disease that has high mortality rates linked to it. Its ability to adapt to environmental stresses through the production of secondary metabolites, including several mycotoxins (gliotoxin, fumagillin, pseurotin A, etc.) also seem to play an important role in causing these infections. Since the discovery of the A. fumigatus fumagillin in 1949, many studies have focused on this toxin and in this review we gather all the information currently available. First of all, the structural characteristics of this mycotoxin and the different methods developed for its determination are given in detail. Then, the biosynthetic gene cluster and the metabolic pathway involved in its production and regulation are explained. The activity of fumagillin on its target, the methionine aminopeptidase type 2 (MetAP2) enzyme, and the effects of blocking this enzyme in the host are also described. Finally, the applications that this toxin and its derivatives have in different fields, such as the treatment of cancer and its microsporicidal activity in the treatment of honeybee hive infections with Nosema spp., are reviewed. Therefore, this work offers a complete review of all the information currently related to the fumagillin mycotoxin secreted by A. fumigatus, important because of its role in the fungal infection process but also because it has many other applications, notably in beekeeping, the treatment of infectious diseases, and in oncology. Key Contribution:Fumagillin is a mycotoxin produced during infections caused by A. fumigatus and in the adaptation processes of this species to multiple environmental stresses. In this review; we include detailed information on the fungal mechanisms employed in the production of this mycotoxin and those present in its regulation, how it acts on its target, and how it can be detected, all of which may be useful for diagnosis or the development of new treatments. Its usefulness in different fields is also described; because of its anti-angiogenic activity it is used to attack different types of tumors; at the same time its antibiotic activity is useful against several parasites.

show abstract

“…β-(1,3)-D-Glucan synthase (GS) is a vital enzyme in the synthesis of the essential component of the fungal cell wall, β-(1,3)-D-glucan. Cells exposed to echinocandin B (shows morphological changes such as swelling and release of intracellular contents ( Eshwika et al, 2013 ). Echinocandins act as specific, non-competitive inhibitors of GS.…”

Section: Antifungal Treatment Strategiesmentioning

confidence: 99%

Prospects for anti-Candida therapy through targeting the cell wall: A mini-review

2021

View full text Add to dashboard Cite

The impact of fungal infections on humans is a serious public health issue that has received much less attention than bacterial infection and treatment, despite ever-increasing incidence exacerbated by an increased incidence of immunocompromised individuals in the population. Candida species, in particular, cause some of the most prevalent hospital-related fungal infections. Fungal infections are also detrimental to the well-being of grazing livestock, with milk production in dairy cows, and body and coat condition adversely affected by fungal infections. Fungal cell walls are essential for viability, morphogenesis and pathogenesis: numerous anti-fungal drugs rely on targeting either the cell wall or cell membrane, but the pipeline of available bioactives is limited. There is a clear and unmet need to identify novel targets and develop new classes of anti-fungal agents. This mini review focuses on fungal cell wall structure, composition and biosynthesis in Candida spp., including C. auris . In addition, an overview of current advances in the development of cell wall targeted therapies is considered.

show abstract

Exposure of Aspergillus fumigatus to caspofungin results in the release, and de novo biosynthesis, of gliotoxin

Cited by 5 publications

References 24 publications

Module-detection approaches for the integration of multilevel omics data highlight the comprehensive response of Aspergillus fumigatus to caspofungin

Module-detection approaches for the integration of multilevel omics data highlight the comprehensive response of Aspergillus fumigatus to caspofungin

Fumagillin, a Mycotoxin of Aspergillus fumigatus: Biosynthesis, Biological Activities, Detection, and Applications

Prospects for anti-Candida therapy through targeting the cell wall: A mini-review

Contact Info

Product

Resources

About