Antifungal Activity of Siderophore Isolated From Escherichia coli Against Aspergillus nidulans via Iron-Mediated Oxidative Stress (original) (raw)
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Siderophore in fungal physiology and virulence
Journal of Pharmacognosy and Phytochemistry, 2017
The iron plays free catalytic role in various vital cellular reactions and is not freely available in the environment due to host sequestration Maintaining the appropriate balance of iron between deficiency and toxicity requires fixed tuned-control system for iron uptake and storage. Most fungi express specific mechanism for acquisition of iron from the hosts they infect for their own survival. Siderophores, a low molecular weight iron chelator has the ability to form very stable and soluble complexes with iron. High affinity iron uptake systems such as siderophores mediated iron uptake and reductive iron assimilation (RIA) enable fungi to acquire limited iron from plant and animal host. Regulating the iron uptake is crucial to maintain iron homeostasis, a state necessary to avoid iron toxicity from iron abundance and simultaneously supply iron required to meet biochemical demand. Fungal cell used two different strategies to regulate iron acquisition that are activation during iron ...
Fungal siderophores: structures, functions and applications
Mycological Research, 2002
Siderophores are low molecular weight, iron-chelating ligands produced by nearly all microorganisms. Fungi synthesize a wide range of hydroxamate siderophores. This review considers the chemical and biological aspects of these siderophores, their distribution amongst fungal genera and their possible applications. Siderophores function primarily as iron transport compounds. Expression of siderophore biosynthesis and the uptake systems is regulated by internal iron concentrations. Transport of siderophores is an energy-dependent process and is stereoselective, depending on recognition of the metal ion coordination geometry. In addition to transporting iron, siderophores have other functions and effects, including enhancing pathogenicity, acting as intracellular iron storage compounds and suppressing growth of other microorganisms. Siderophores can complex other metals apart from iron, in particular the actinides. Because of their metal-binding ability there are potential applications for siderophores in medicine, reprocessing of nuclear fuel, remediation of metalcontaminated sites and the treatment of industrial waste.
Extracellular Siderophores fromAspergillus ochraceous
A large numberofiron-chelating compounds (siderophores) wereisolated fromsupernatants ofiron- deficient cultures ofamoldisolate, subsequently identified asAspergillus ochraceous. Siderophores intheir iron chelate formwerepurified tohomogeneity byusing Bio-Gel P2,silica gel, andC-18bonded silica gel (reverse-phase) columns. Mostofthese compounds, asidentified by'Hand13Cnuclear magnetic resonance spectroscopy andX-raycrystallography, belong totheferrichrome family. Theorganism produces ferrirubin andferrichrysin asthepredominant andthesecond major compound (62and15%ofthetotal siderophores), respectively. Ferrichrysin appears asthefirst siderophore inthemediumonday2ofgrowth. Several oftheother siderophores arenovel andranged inquantities from0.2to5%ofthetotal. Thetrivial namesasperchrome A,Bi,B2,C,DI,D2,andD3areproposed forthese novel compounds, whichareall membersoftheferrichrome family, andallbutthefirst onecontain acommonOrn,-Orn2-Orn3-Ser1-Ser2- Glycyclic hexapeptide ringwithth...
Letters in Applied Microbiology, 2009
Aims: Aspergillus fumigatus is the most common cause of airborne mould infections in immunocompromised patients worldwide. Our aim was to develop a method to identify agents that inhibit siderophore biosynthesis because this pathway is unique to the fungus and is essential for virulence. Methods and Results: A high-throughput two-step screening assay was developed using 96-well plates in which fungal growth and siderophore production is assessed spectrophotometrically. If a compound inhibits growth only in iron-limited medium (screen 1), its effect on siderophore production is then determined (screen 2). The proof of concept was demonstrated using a known antifungal agent, amphotericin B, and a strain of A. fumigatus deficient in siderophore production. Conclusions: The two-stage screening method clearly identified growth defects in A. fumigatus related specifically to siderophore biosynthesis. Significance and Impact of the Study: The increasing incidence of life-threatening fungal infections has produced an urgent need for novel antifungal agents. The method described in this report will facilitate the identification of novel antifungal compounds that inhibit a pathway critical for A. fumigatus virulence and have a reduced probability of affecting host metabolism.
Distinct Roles for Intra- and Extracellular Siderophores during Aspergillus fumigatus Infection
PLOS Pathogens, 2007
Siderophore biosynthesis by the highly lethal mould Aspergillus fumigatus is essential for virulence, but non-existent in humans, presenting a rare opportunity to strategize therapeutically against this pathogen. We have previously demonstrated that A. fumigatus excretes fusarinine C and triacetylfusarinine C to capture extracellular iron, and uses ferricrocin for hyphal iron storage. Here, we delineate pathways of intra-and extracellular siderophore biosynthesis and show that A. fumigatus synthesizes a developmentally regulated fourth siderophore, termed hydroxyferricrocin, employed for conidial iron storage. By inactivation of the nonribosomal peptide synthetase SidC, we demonstrate that the intracellular siderophores are required for germ tube formation, asexual sporulation, resistance to oxidative stress, catalase A activity, and virulence. Restoration of the conidial hydroxyferricrocin content partially rescues the virulence of the apathogenic siderophore null mutant DsidA, demonstrating an important role for the conidial siderophore during initiation of infection. Abrogation of extracellular siderophore biosynthesis following inactivation of the acyl transferase SidF or the nonribosomal peptide synthetase SidD leads to complete dependence upon reductive iron assimilation for growth under iron-limiting conditions, partial sensitivity to oxidative stress, and significantly reduced virulence, despite normal germ tube formation. Our findings reveal distinct cellular and disease-related roles for intraand extracellular siderophores during mammalian Aspergillus infection. Citation: Schrettl M, Bignell E, Kragl C, Sabiha Y, Loss O, et al. (2007) Distinct roles for intra-and extracellular siderophores during Aspergillus fumigatus infection. PLoS Pathog 3(9): e128.
Biosynthesis Pathways, Transport Mechanisms and Biotechnological Applications of Fungal Siderophores
Journal of Fungi, 2022
Iron (Fe) is the fourth most abundant element on earth and represents an essential nutrient for life. As a fundamental mineral element for cell growth and development, iron is available for uptake as ferric ions, which are usually oxidized into complex oxyhydroxide polymers, insoluble under aerobic conditions. In these conditions, the bioavailability of iron is dramatically reduced. As a result, microorganisms face problems of iron acquisition, especially under low concentrations of this element. However, some microbes have evolved mechanisms for obtaining ferric irons from the extracellular medium or environment by forming small molecules often regarded as siderophores. Siderophores are high affinity iron-binding molecules produced by a repertoire of proteins found in the cytoplasm of cyanobacteria, bacteria, fungi, and plants. Common groups of siderophores include hydroxamates, catecholates, carboxylates, and hydroximates. The hydroxamate siderophores are commonly synthesized by fungi. L-ornithine is a biosynthetic precursor of siderophores, which is synthesized from multimodular large enzyme complexes through non-ribosomal peptide synthetases (NRPSs), while siderophore-Fe chelators cell wall mannoproteins (FIT1, FIT2, and FIT3) help the retention of siderophores. S. cerevisiae, for example, can express these proteins in two genetically separate systems (reductive and nonreductive) in the plasma membrane. These proteins can convert Fe (III) into Fe (II) by a ferrous-specific metalloreductase enzyme complex and flavin reductases (FREs). However, regulation of the siderophore through Fur Box protein on the DNA promoter region and its activation or repression depend primarily on the Fe availability in the external medium. Siderophores are essential due to their wide range of applications in biotechnology, medicine, bioremediation of heavy metal polluted environments, biocontrol of plant pathogens, and plant growth enhancement.
Applied Microbiology and Biotechnology, 2003
To acquire iron, all species have to overcome the problems of iron insolubility and toxicity. In response to low iron availability in the environment, most fungi excrete ferric iron-specific chelators-siderophores-to mobilize this metal. Siderophore-bound iron is subsequently utilized via the reductive iron assimilatory system or uptake of the siderophore-iron complex. Furthermore, most fungi possess intracellular siderophores as iron storage compounds. Molecular analysis of siderophore biosynthesis was initiated by pioneering studies on the basidiomycete Ustilago maydis, and has progressed recently by characterization of the relevant structural and regulatory genes in the ascomycetes Aspergillus nidulans and Neurospora crassa. In addition, significant advances in the understanding of utilization of siderophore-bound iron have been made recently in the yeasts Saccharomyces cerevisiae and Candida albicans as well as in the filamentous fungus A. nidulans. The present review summarizes molecular details of fungal siderophore biosynthesis and uptake, and the regulatory mechanisms involved in control of the corresponding genes.
Journal of Biological Chemistry, 1999
A gene encoding a new GATA factor from Aspergillus nidulans, sreA, was isolated and characterized. SREA displays homology to two fungal regulators of siderophore biosynthesis: about 30% overall identity to SRE from Neurospora crassa and about 50% identity to URBS1 from Ustilago maydis over a stretch of 200 amino acid residues containing two GATA-type zinc finger motifs and a cysteine-rich region. This putative DNA binding domain, expressed as a fusion protein in Escherichia coli, specifically binds to GATA sequence motifs. Deletion of sreA results in derepression of L-ornithine-N 5oxygenase activity and consequently in derepression of the biosynthesis of the hydroxamate siderophore N,N,N-triacetyl fusarinine under sufficient iron supply in A. nidulans. Transcription of sreA is confined to high iron conditions, underscoring the function of SREA as a repressor of siderophore biosynthesis under sufficient iron supply. Nevertheless, overexpression of sreA does not result in repression of siderophore synthesis under low iron conditions, suggesting additional mechanisms involved in this regulatory circuit. Consistent with increased sensitivity to the iron-activated antibiotics phleomycin and streptonigrin, the sreA deletion mutant displays increased accumulation of 59 Fe. These results demonstrate that SREA plays a central role in iron uptake in addition to siderophore biosynthesis.
Biochemical Society Transactions, 2001
Iron is an essential trace element for almost all organisms. However, an excess of this metal within cells can be deleterious on account of catalysis of cell-damaging hydroxyl radicals. Therefore, the concentration of iron within cells is tightly regulated and the primary control occurs by regulating its uptake. Under conditions of low iron availability, most fungi mobilize extracellular iron by excretion of low-molecular-mass ferric iron chelators, termed siderophores. Due to the potential impact of iron metabolism on fungal pathogenicity, a better insight into siderophore-mediated iron uptake is needed. In Aspergillus nidulans, siderophore biosynthesis and uptake are negatively regulated by the GATA-type transcription factor SREA. Hence, genes involved in siderophore biosynthesis and uptake are characterized by transcriptional induction under iron limitation in wild-type strain and de-repression in an sreA-deletion strain under conditions of sufficient iron supply. Such genes have...