Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Polycatechol-based iron predators disrupt fungal iron homeostasis to drive selective antifungal action

ABSTRACT: Fungal infections pose a growing global health challenge, exacerbated by a scarcity of effective treatments and rising drug resistance. Although cationic polymers emerge as promising antifungal candidates owing to structural tunability, design flexibility, and resistance to proteolytic degradation, their clinical utility has been hampered by non-selective membrane-disruption mechanisms. Herein, we develop a class of polycatechols- termed fungal iron predators (FIPs), exhibit exceptional fungicidal activity and markedly low cytotoxicity. These FIPs can efficiently infiltrate fungal cells, selectively sequester labile irons, and disrupt iron homeostasis and metabolism. The ensuing iron starvation provokes severe mitochondrial dysfunction and energy collapse, culminating in fungal cell death. Through systemic optimization of cationic density and catechol stoichiometry, we obtained an FIP variant demonstrating potent antifungal activity with high selectivity toward fungi over mammalian cells, minimal propensity to induce resistance, and supplementary antioxidant properties. Remarkably, this FIP candidate shows robust therapeutic performance across multiple in vivo models of fungal infection. Critically, this work established a groundbreaking paradigm in polymer design: shifting the antifungal mechanism from traditional non-specific membrane disruption to targeted intracellular metabolic interference. The general applicability of this strategy across diverse cationic polymer backbones opens avenues for developing next generation of precision antifungal agents.

ORGANISM(S): Candida albicans

PROVIDER: GSE327028 | GEO | 2026/06/03

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Acidic pH Reduces Fluconazole Susceptibility in Cryptococcus neoformans by Altering Iron Uptake and Enhancing Ergosterol Biosynthesis

Project description:The opportunistic fungal pathogen Cryptococcus neoformans faces a wide range of environmental pH within the host, and adaptation to different pH conditions plays a critical role in their survival and pathogenesis. In the current study, how environmental pH influences antifungal susceptibility and iron uptake in C. neoformans was investigated. We found that acidic pH conditions significantly reduced antifungal susceptibility of C. neoformans to fluconazole. Moreover, our study revealed that iron acquisition in C. neoformans at acidic pH is independent of the high-affinity iron uptake system, and leads to increase of intracellular iron accumulation, increased ergosterol and heme levels, which may contribute to reduced fluconazole susceptibility of the fungus. Transcriptome analysis further elucidated the molecular mechanisms underlying the pH-dependent shift of iron uptake and antifungal susceptibility of C. neoformans. Our findings highlight the importance of environmental pH in physiology and pathogenesis of C. neoformans and provide insights into developing novel treatment for cryptococcosis.

2025-03-18 | GSE291861 | GEO

Differentially expressed genes of cir1 mutants in low iron or high iron medium

Project description:Iron overload is known to exacerbate many infectious diseases and, conversely, iron withholding is an important defense strategy for mammalian hosts. The mechanisms by which fungal pathogens sense iron in the mammalian host environment are poorly understood. The AIDS-associated pathogen Cryptococcus neoformans provides a unique opportunity to explore iron sensing in the context of infection because iron levels control elaboration of the polysaccharide capsule that is the major virulence factor of the fungus. Additionally, excess iron exacerbates experimental cryptococcosis. We identified the iron-responsive transcription factor Cir1 that regulates iron acquisition in C. neoformans and discovered that Cir1 also controls the expression of all of the known major virulence factors of the fungus. In particular, cir1 mutants are defective in capsule formation and avirulent in a mouse model of cryptococcosis. Thus the ability to sense iron is critical during infection by C. neoformans and may represent a target for antifungal therapy. Keywords: wt/mutant x low/high iron

2006-09-14 | GSE5341 | GEO

iron response-Transcriptomic response to iron signaling

Project description:no27_iron_signaling - iron response - Effect of exceed of Iron - Time course experiment, star design and 3 biological repeats. Keywords: time course

2007-06-20 | GSE7983 | GEO

Genome-wide transcriptional changes under oxidative stress in iron-starved Aspergillus fumigatus cultures

Project description:Aspergillus fumigatus has to cope with a combination of several stress types in the human body, and the interplay between the different stress responses can significantly influence the survival of this human pathogen during the invasion of the host organism. In this study, we examined how the H2O2 induced oxidative stress response depends on iron availability. Surprisingly, the applied H2O2 treatment, which induced only a negligible stress response in iron fed cultures, deleteriously affected the fungus under iron starvation and the majority of observed transcriptome-level stress responses were characteristic only for the combined H2O2-iron starvation stress treatments. Our data suggest that the survival of the fungus highly depended on fragile balances, e.g. between siderophore and ergosterol productions or between economization on iron and production of essential iron containing proteins. The applied stress conditions also affected several processes related to virulence or drug susceptibility including secondary metabolism, zinc acquisition or antifungal drug transport. Our data clearly demonstrate that studying stress responses under single stress treatments is not sufficient at all to understand how fungal pathogens survive in a complex habitat and support the view that the evolutionary success of A. fumigatus as an opportunistic human pathogen is not the mere consequence of the productions of certain virulence factors. Importantly, this fungal pathogen is able to mount and coordinate high-complexity and outstandingly efficient responses to multiple and superpositioning stresses in various harsh habitats like the human body.

2018-01-01 | GSE94818 | GEO

Targeting Iron - Respiratory Reciprocity Promotes Bacterial Death

Project description:Discovering new bacterial signaling pathways offers unique antibiotic strategies. Here, through an unbiased resistance screen of 3,884 gene knockout strains, we uncovered a previously unknown non-lytic bactericidal mechanism that sequentially couples three transporters and downstream transcription to lethally suppress respiration of the highly virulent P. aeruginosa strain PA14 - one of three species on the WHO's 'Priority 1: Critical' list. By targeting outer membrane YaiW, cationic lacritin peptide 'N-104' translocates into the periplasm where it ligates outer loops 4 and 2 respectively of the inner membrane transporters FeoB and PotH to respectively suppress both ferrous iron and polyamine uptake. This broadly shuts down transcription of many biofilm-associated genes, including ferrous iron-dependent TauD and ExB1. The mechanism is innate to the surface of the eye enhanced by synergistic coupling with thrombin peptide GKY20. This is the first example of an inhibitor of multiple bacterial transporters.

2024-01-16 | GSE253123 | GEO

Transcriptomics analysis of amphotericin B and lactoferrin drug synergy in Cryptococcus neoformans H99

Project description:Invasive fungal infections (IFIs) are difficult to treat. Few effective antifungal drugs are available and many have problems with toxicity, efficacy and drug-resistance. To overcome these challenges, existing therapies may be enhanced using more than one agent acting in synergy. Previously, we have found amphotericin B (AMB) and the iron chelator, lactoferrin (LF), were synergistic against Cryptococcus neoformans and Saccharomyces cerevisiae. This study investigates the mechanism of AMB+LF synergy using RNA-seq in Cryptococcus neoformans H99.

2019-09-08 | GSE130375 | GEO

Genome wide expression responses of Fusarium oxysporum wt and ΔhapX mutant to iron depleted and iron replete conditions.

Project description:Soilborne fungal pathogens cause devastating yield losses, are highly persistent and difficult to control. To culminate infection, these organisms must cope with limited availability of iron. Here we show that the bZIP protein HapX functions as a key regulator of iron homeostasis and virulence in the vascular wilt fungus Fusarium oxysporum. Deletion of hapX does not affect iron uptake, but causes derepression of genes involved in iron-consuming pathways, leading to impaired growth under iron-depleted conditions. F. oxysporum strains lacking HapX are reduced in their capacity to invade and kill tomato plants and immunodepressed mice. The virulence defect of ΔhapX on tomato plants is exacerbated by coinoculation of roots with a biocontrol strain of Pseudomonas putida, but not with a siderophore-deficient mutant, indicating that HapX contributes to iron competition of F. oxysporum in the tomato rhizosphere. These results establish a conserved role for HapX-mediated iron homeostasis in fungal infection of plants and mammals.

2012-07-14 | GSE39325 | GEO

Role of IdeR in Iron-Dependent Gene Expression, Iron Metabolism, and Oxidative Stress Response

Project description:The mycobacterial IdeR protein is a metal-dependent regulator of the DtxR (diphtheria toxin repressor) family. In the presence of iron, it binds to a specific DNA sequence in the promoter regions of the genes that it regulates, thus controlling their transcription. In this study, we provide evidence that ideR is an essential gene in Mycobacterium tuberculosis. ideR cannot normally be disrupted in this mycobacterium in the absence of a second functional copy of the gene. However, a rare ideR mutant was obtained in which the lethal effects of ideR inactivation were alleviated by a second-site suppressor mutation and which exhibited restricted iron assimilation capacity. Studies of this strain and a derivative in which IdeR expression was restored allowed us to identify phenotypic effects resulting from ideR inactivation. Using DNA microarrays, the iron-dependent transcriptional profiles of the wild-type, ideR mutant, and ideR complemented mutant strains were analyzed, and the genes regulated by iron and IdeR were identified. These genes encode a variety of proteins, including putative transporters, proteins involved in siderophore synthesis and iron storage, members of the PE/PPE family, a membrane protein involved in virulence, transcriptional regulators, and enzymes involved in lipid metabolism. Keywords: strain or line design, genetic modification design, comparative genome hybridization design and stimulus or stress design

2007-08-09 | GSE8732 | GEO

Genome wide expression responses of Fusarium oxysporum wt and M-NM-^ThapX mutant to iron depleted and iron replete conditions.

Project description:Soilborne fungal pathogens cause devastating yield losses, are highly persistent and difficult to control. To culminate infection, these organisms must cope with limited availability of iron. Here we show that the bZIP protein HapX functions as a key regulator of iron homeostasis and virulence in the vascular wilt fungus Fusarium oxysporum. Deletion of hapX does not affect iron uptake, but causes derepression of genes involved in iron-consuming pathways, leading to impaired growth under iron-depleted conditions. F. oxysporum strains lacking HapX are reduced in their capacity to invade and kill tomato plants and immunodepressed mice. The virulence defect of M-NM-^ThapX on tomato plants is exacerbated by coinoculation of roots with a biocontrol strain of Pseudomonas putida, but not with a siderophore-deficient mutant, indicating that HapX contributes to iron competition of F. oxysporum in the tomato rhizosphere. These results establish a conserved role for HapX-mediated iron homeostasis in fungal infection of plants and mammals. Iron dependent gene expression in Fusarium oxysporum wt and M-NM-^ThapX mutant was measured 1 hour after shifting the mycelia to minimal medium with or without 50 M-NM-<M Fe2(SO4)3. Three independent experiments were performed.

2012-07-13 | E-GEOD-39325 | biostudies-arrayexpress

Aspergillus fumigatus ZnfA, a novel zinc finger transcription factor involved in calcium metabolism and caspofungin tolerance

Project description:Invasive Pulmonary Aspergillosis (IPA) is a life-threatening fungal infection especially in immunocompromised population. The low availability of antifungal drugs coupled with the emergence of antifungal resistance has become an important clinical concern. Caspofungin (CSP) is recommended as second-line therapy but resistance and tolerance mechanisms have been reported. However, how the fungal cell articulates the response to CSP is not completely understood. In this work we have characterized ZnfA, a new transcription factor (TF) identified in previous screening studies that is involved in calcium and CSP A. fumigatus response. This TF plays an important role in iron homeostasis and cell wall organization in response to high CSP concentrations as revealed by Chromatin Immunoprecipitation coupled to DNA sequencing (ChIP-seq) analysis. Furthermore, ZnfA acts collaboratively with the key TF CrzA in the response to calcium, cell wall and osmotic stresses. Thus, this study increases our knowledge about the link between calcium signaling and the CSP cellular response and exposes the complex connections among different pathways that govern stress sensing in A. fumigatus.

2021-10-04 | GSE167847 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data