Aspergillus fumigatus Survival in Alkaline and Extreme Zinc-Limiting Environments Relies on the Induction of a Zinc Homeostasis System Encoded by the zrfC and aspf2 Genes

ABSTRACTAspergillus fumigatushas three zinc transporter-encoding genes whose expression is regulated by both pH and the environmental concentration of zinc. We have previously reported that thezrfAandzrfBgenes ofA. fumigatusare transcribed at higher levels and are required for fungal growth under acidic zinc-limiting conditions whereas they are dispensable for growth in neutral or alkaline zinc-limiting media. Here we report that the transporter of the zinc uptake system that functions inA. fumigatusgrowing in neutral or alkaline environments is encoded byzrfC. The transcription ofzrfCoccurs divergently with respect to the adjacentaspf2gene, which encodes an immunodominant antigen secreted byA. fumigatus. The two genes—zrfCandaspf2—are required to different extents for fungal growth in alkaline and extreme zinc-limiting media. Indeed, these environmental conditions induce the simultaneous transcription of both genes mediated by the transcriptional regulators ZafA and PacC. ZafA upregulates the expression ofzrfCandaspf2under zinc-limiting conditions regardless of the ambient pH, whereas PacC represses the expression of these genes under acidic growth conditions. Interestingly, the mode of action of PacC forzrfC-aspf2transcription contrasts with the more widely accepted model for PacC function, according to which under alkaline growth conditions PacC would activate the transcription of alkaline-expressed genes but would repress the transcription of acid-expressed genes. In sum, this report provides a good framework for investigating several important aspects of the biology of species ofAspergillus, including the repression of alkaline genes by PacC at acidic pH and the interrelationship that must exist between tissue pH, metal availability in the host tissue, and fungal virulence.

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Dsc Orthologs Are Required for Hypoxia Adaptation, Triazole Drug Responses, and Fungal Virulence in Aspergillus fumigatus

Eukaryotic Cell ◽

10.1128/ec.00252-12 ◽

2012 ◽

Vol 11 (12) ◽

pp. 1557-1567 ◽

Cited By ~ 42

Author(s):

Sven D. Willger ◽

E. Jean Cornish ◽

Dawoon Chung ◽

Brittany A. Fleming ◽

Margaret M. Lehmann ◽

...

Keyword(s):

Aspergillus Fumigatus ◽

Regulatory Element ◽

Invasive Pulmonary Aspergillosis ◽

Fungal Growth ◽

Drug Susceptibility ◽

Antifungal Drugs ◽

Fungal Virulence ◽

Content Type ◽

Hypoxia Adaptation ◽

Element Binding Protein

ABSTRACTHypoxia is an environmental stress encountered byAspergillus fumigatusduring invasive pulmonary aspergillosis (IPA). The ability of this mold to adapt to hypoxia is important for fungal virulence and genetically regulated in part by the sterol regulatory element binding protein (SREBP) SrbA. SrbA is required for fungal growth in the murine lung and to ultimately cause lethal disease in murine models of IPA. Here we identified and partially characterized four genes (dscA,dscB,dscC, anddscD, here referred to asdscA-D) with previously unknown functions inA. fumigatusthat are orthologs of theSchizosaccharomyces pombegenesdsc1,dsc2,dsc3, anddsc4(dsc1-4), which encode a Golgi E3 ligase complex critical for SREBP activation by proteolytic cleavage.A. fumigatusnulldscA-Dmutants displayed remarkable defects in hypoxic growth and increased susceptibility to triazole antifungal drugs. Consistent with the confirmed role of these genes inS. pombe, both ΔdscAand ΔdscCresulted in reduced cleavage of the SrbA precursor protein inA. fumigatus. Inoculation of corticosteroid immunosuppressed mice with ΔdscAand ΔdscCstrains revealed that these genes are critical forA. fumigatusvirulence. Reintroduction of SrbA amino acids 1 to 425, encompassing the N terminus DNA binding domain, into the ΔdscAstrain was able to partially restore virulence, further supporting a mechanistic link between DscA and SrbA function. Thus, we have shown for the first time the importance of a previously uncharacterized group of genes inA. fumigatusthat mediate hypoxia adaptation, fungal virulence, and triazole drug susceptibility and that are likely linked to regulation of SrbA function.

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Aspergillus fumigatus and Aspergillosis in 2019

Clinical Microbiology Reviews ◽

10.1128/cmr.00140-18 ◽

2019 ◽

Vol 33 (1) ◽

Cited By ~ 74

Author(s):

Jean-Paul Latgé ◽

Georgios Chamilos

Keyword(s):

Aspergillus Fumigatus ◽

Current Status ◽

Fungal Virulence ◽

Content Type ◽

Nutritional Immunity ◽

New Concepts ◽

Clinical Syndromes ◽

Metabolic Activities ◽

Primary Habitat ◽

Hostile Environments

SUMMARY Aspergillus fumigatus is a saprotrophic fungus; its primary habitat is the soil. In its ecological niche, the fungus has learned how to adapt and proliferate in hostile environments. This capacity has helped the fungus to resist and survive against human host defenses and, further, to be responsible for one of the most devastating lung infections in terms of morbidity and mortality. In this review, we will provide (i) a description of the biological cycle of A. fumigatus; (ii) a historical perspective of the spectrum of aspergillus disease and the current epidemiological status of these infections; (iii) an analysis of the modes of immune response against Aspergillus in immunocompetent and immunocompromised patients; (iv) an understanding of the pathways responsible for fungal virulence and their host molecular targets, with a specific focus on the cell wall; (v) the current status of the diagnosis of different clinical syndromes; and (vi) an overview of the available antifungal armamentarium and the therapeutic strategies in the clinical context. In addition, the emergence of new concepts, such as nutritional immunity and the integration and rewiring of multiple fungal metabolic activities occurring during lung invasion, has helped us to redefine the opportunistic pathogenesis of A. fumigatus.

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Three Related Enzymes in Candida albicans Achieve Arginine- and Agmatine-Dependent Metabolism That Is Essential for Growth and Fungal Virulence

mBio ◽

10.1128/mbio.01845-20 ◽

2020 ◽

Vol 11 (4) ◽

Author(s):

Katja Schaefer ◽

Jeanette Wagener ◽

Ryan M. Ames ◽

Stella Christou ◽

Donna M. MacCallum ◽

...

Keyword(s):

Candida Albicans ◽

Amino Acid ◽

Galleria Mellonella ◽

Fungal Growth ◽

Open Reading Frames ◽

Mammalian Host ◽

No Production ◽

Triple Mutant ◽

Fungal Virulence ◽

Content Type

ABSTRACT Amino acid metabolism is crucial for fungal growth and development. Ureohydrolases produce amines when acting on l-arginine, agmatine, and guanidinobutyrate (GB), and these enzymes generate ornithine (by arginase), putrescine (by agmatinase), or GABA (by 4-guanidinobutyrase or GBase). Candida albicans can metabolize and grow on arginine, agmatine, or guanidinobutyrate as the sole nitrogen source. Three related C. albicans genes whose sequences suggested that they were putative arginase or arginase-like genes were examined for their role in these metabolic pathways. Of these, Car1 encoded the only bona fide arginase, whereas we provide evidence that the other two open reading frames, orf19.5862 and orf19.3418, encode agmatinase and guanidinobutyrase (Gbase), respectively. Analysis of strains with single and multiple mutations suggested the presence of arginase-dependent and arginase-independent routes for polyamine production. CAR1 played a role in hyphal morphogenesis in response to arginine, and the virulence of a triple mutant was reduced in both Galleria mellonella and Mus musculus infection models. In the bloodstream, arginine is an essential amino acid that is required by phagocytes to synthesize nitric oxide (NO). However, none of the single or multiple mutants affected host NO production, suggesting that they did not influence the oxidative burst of phagocytes. IMPORTANCE We show that the C. albicans ureohydrolases arginase (Car1), agmatinase (Agt1), and guanidinobutyrase (Gbu1) can orchestrate an arginase-independent route for polyamine production and that this is important for C. albicans growth and survival in microenvironments of the mammalian host.

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Coordinated Zinc Homeostasis Is Essential for the Wild-Type Virulence of Brucella abortus

Journal of Bacteriology ◽

10.1128/jb.02543-14 ◽

2015 ◽

Vol 197 (9) ◽

pp. 1582-1591 ◽

Cited By ~ 15

Author(s):

Lauren M. Sheehan ◽

James A. Budnick ◽

R. Martin Roop ◽

Clayton C. Caswell

Keyword(s):

Mouse Model ◽

Brucella Abortus ◽

Zinc Uptake ◽

Zinc Homeostasis ◽

Zinc Toxicity ◽

Uptake System ◽

Bacterial Cells ◽

Gene Encoding ◽

Content Type ◽

Genes Encoding

ABSTRACTMetal homeostasis in bacterial cells is a highly regulated process requiring intricately coordinated import and export, as well as precise sensing of intracellular metal concentrations. The uptake of zinc (Zn) has been linked to the virulence ofBrucella abortus; however, the capacity ofBrucellastrains to sense Zn levels and subsequently coordinate Zn homeostasis has not been described. Here, we show that expression of the genes encoding the zinc uptake system ZnuABC is negatively regulated by the Zn-sensing Fur family transcriptional regulator, Zur, by direct interactions between Zur and the promoter region ofznuABC. Moreover, the MerR-type regulator, ZntR, controls the expression of the gene encoding the Zn exporter ZntA by binding directly to its promoter. Deletion ofzurorzntRalone did not result in increased zinc toxicity in the corresponding mutants; however, deletion ofzntAled to increased sensitivity to Zn but not to other metals, such as Cu and Ni, suggesting that ZntA is a Zn-specific exporter. Strikingly, deletion ofzntRresulted in significant attenuation ofB. abortusin a mouse model of chronic infection, and subsequent experiments revealed that overexpression ofzntAin thezntRmutant is the molecular basis for its decreased virulence.IMPORTANCEThe importance of zinc uptake forBrucellapathogenesis has been demonstrated previously, but to date, there has been no description of how overall zinc homeostasis is maintained and genetically controlled in the brucellae. The present work defines the predominant zinc export system, as well as the key genetic regulators of both zinc uptake and export inBrucella abortus. Moreover, the data show the importance of precise coordination of the zinc homeostasis systems as disregulation of some elements of these systems leads to the attenuation ofBrucellavirulence in a mouse model. Overall, this study advances our understanding of the essential role of zinc in the pathogenesis of intracellular bacteria.

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Laccases Involved in 1,8-Dihydroxynaphthalene Melanin Biosynthesis in Aspergillus fumigatus Are Regulated by Developmental Factors and Copper Homeostasis

Eukaryotic Cell ◽

10.1128/ec.00217-13 ◽

2013 ◽

Vol 12 (12) ◽

pp. 1641-1652 ◽

Cited By ~ 44

Author(s):

Srijana Upadhyay ◽

Guadalupe Torres ◽

Xiaorong Lin

Keyword(s):

Immune Responses ◽

Aspergillus Fumigatus ◽

Gene Cluster ◽

Gene Expression Pattern ◽

Copper Homeostasis ◽

Copper Level ◽

Fungal Virulence ◽

Copper Transporter ◽

Melanin Biosynthesis ◽

Content Type

ABSTRACTAspergillus fumigatusproduces heavily melanized infectious conidia. The conidial melanin is associated with fungal virulence and resistance to various environmental stresses. This 1,8-dihydroxynaphthalene (DHN) melanin is synthesized by enzymes encoded in a gene cluster inA. fumigatus, including two laccases, Abr1 and Abr2. Although this gene cluster is not conserved in all aspergilli, laccases are critical for melanization in all species examined. Here we show that the expression ofA. fumigatuslaccases Abr1/2 is upregulated upon hyphal competency and drastically increased during conidiation. The Abr1 protein is localized at the surface of stalks and conidiophores, but not in young hyphae, consistent with the gene expression pattern and its predicted role. The induction of Abr1/2 upon hyphal competency is controlled by BrlA, the master regulator of conidiophore development, and is responsive to the copper level in the medium. We identified a developmentally regulated putative copper transporter, CtpA, and found that CtpA is critical for conidial melanization under copper-limiting conditions. Accordingly, disruption of CtpA enhanced the induction ofabr1andabr2, a response similar to that induced by copper starvation. Furthermore, nonpigmentedctpAΔ conidia elicited much stronger immune responses from the infected invertebrate hostGalleria mellonellathan the pigmentedctpAΔ or wild-type conidia. Such enhancement in elicitingGalleriaimmune responses was independent of thectpAΔ conidial viability, as previously observed for the DHN melanin mutants. Taken together, our findings indicate that both copper homeostasis and developmental regulators control melanin biosynthesis, which affects conidial surface properties that shape the interaction between this pathogen and its host.

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The Volatome of Aspergillus fumigatus

Eukaryotic Cell ◽

10.1128/ec.00074-14 ◽

2014 ◽

Vol 13 (8) ◽

pp. 1014-1025 ◽

Cited By ~ 61

Author(s):

C. Heddergott ◽

A. M. Calvo ◽

J. P. Latgé

Keyword(s):

Aspergillus Fumigatus ◽

Growth Conditions ◽

Terpene Biosynthesis ◽

Content Type ◽

Volatile Organic ◽

Volatile Terpenes ◽

Nutritional Environment ◽

Volatile Production ◽

Related Compounds

ABSTRACT Early detection of invasive aspergillosis is absolutely required for efficient therapy of this fungal infection. The identification of fungal volatiles in patient breath can be an alternative for the detection of Aspergillus fumigatus that still remains problematic. In this work, we investigated the production of volatile organic compounds (VOCs) by A. fumigatus in vitro , and we show that volatile production depends on the nutritional environment. A. fumigatus produces a multiplicity of VOCs, predominantly terpenes and related compounds. The production of sesquiterpenoid compounds was found to be strongly induced by increased iron concentrations and certain drugs, i.e., pravastatin. Terpenes that were always detectable in large amounts were α-pinene, camphene, and limonene, as well as sesquiterpenes, identified as α-bergamotene and β- trans -bergamotene. Other substance classes that were found to be present in the volatome, such as 1-octen-3-ol, 3-octanone, and pyrazines, were found only under specific growth conditions. Drugs that interfere with the terpene biosynthesis pathway influenced the composition of the fungal volatome, and most notably, a block of sesquiterpene biosynthesis by the bisphosphonate alendronate fundamentally changed the VOC composition. Using deletion mutants, we also show that a terpene cyclase and a putative kaurene synthase are essential for the synthesis of volatile terpenes by A. fumigatus . The present analysis of in vitro volatile production by A. fumigatus suggests that VOCs may be used in the diagnosis of infections caused by this fungus.

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Phosphoproteomics of Aspergillus fumigatus Exposed to the Antifungal Drug Caspofungin

mSphere ◽

10.1128/msphere.00365-20 ◽

2020 ◽

Vol 5 (3) ◽

Author(s):

Eliciane Cevolani Mattos ◽

Giuseppe Palmisano ◽

Gustavo H. Goldman

Keyword(s):

Cell Wall ◽

Transcription Factors ◽

Aspergillus Fumigatus ◽

Protein Kinases ◽

Pathogenic Fungus ◽

Fungal Growth ◽

Wild Type ◽

Content Type ◽

Mitogen Activated Protein ◽

High Concentrations

ABSTRACT Aspergillus fumigatus is an opportunistic and allergenic pathogenic fungus, responsible for fungal infections in humans. A. fumigatus infections are usually treated with polyenes, azoles, or echinocandins. Echinocandins, such as caspofungin, can inhibit the biosynthesis of the β-1,3-glucan polysaccharide, affecting the integrity of the cell wall and leading to fungal death. In some A. fumigatus strains, caspofungin treatment at high concentrations induces an increase of fungal growth, a phenomenon called the caspofungin paradoxical effect (CPE). Here, we analyze the proteome and phosphoproteome of the A. fumigatus wild-type strain and of mitogen-activated protein kinase (MAPK) mpkA and sakA null mutant strains during CPE (2 μg/ml caspofungin for 1 h). The wild-type proteome showed 75 proteins and 814 phosphopeptides (corresponding to 520 proteins) altered in abundance in response to caspofungin treatment. The ΔmpkA (ΔmpkA caspofungin/wild-type caspofungin) and ΔsakA (ΔsakA caspofungin/wild-type caspofungin) strains displayed 626 proteins and 1,236 phosphopeptides (corresponding to 703 proteins) and 101 proteins and 1,217 phosphopeptides (corresponding to 645 proteins), respectively, altered in abundance. Functional characterization of the phosphopeptides from the wild-type strain exposed to caspofungin showed enrichment for transcription factors, protein kinases, and cytoskeleton proteins. Proteomic analysis of the ΔmpkA and ΔsakA mutants indicated that control of proteins involved in metabolism, such as in production of secondary metabolites, was highly represented in both mutants. Results of functional categorization of phosphopeptides from both mutants were very similar and showed a high number of proteins with decreased phosphorylation of proteins involved in transcriptional control, DNA/RNA binding, cell cycle control, and DNA processing. This report reveals novel transcription factors involved in caspofungin tolerance. IMPORTANCE Aspergillus fumigatus is an opportunistic human-pathogenic fungus causing allergic reactions or systemic infections, such as invasive pulmonary aspergillosis in immunocompromised patients. Caspofungin is an echinocandin that impacts the construction of the fungal cell wall by inhibiting the biosynthesis of the β-1,3-glucan polysaccharide. Caspofungin is a fungistatic drug and is recommended as a second-line therapy for treatment of aspergillosis. Treatment at high concentrations induces an increase of fungal growth, a phenomenon called the caspofungin paradoxical effect (CPE). Collaboration between the mitogen-activated protein kinases (MAPK) of the cell wall integrity (MapkA) and high-osmolarity glycerol (SakA) pathways is essential for CPE. Here, we investigate the global proteome and phosphoproteome of A. fumigatus wild-type, ΔmpkA, and ΔsakA strains upon CPE. This study showed intense cross talk between the two MAPKs for the CPE and identified novel protein kinases and transcription factors possibly important for CPE. Increased understanding of how the modulation of protein phosphorylation may affect the fungal growth in the presence of caspofungin represents an important step in the development of new strategies and methods to combat the fungus inside the host.

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Distinct Roles of Myosins in Aspergillus fumigatus Hyphal Growth and Pathogenesis

Infection and Immunity ◽

10.1128/iai.01190-15 ◽

2016 ◽

Vol 84 (5) ◽

pp. 1556-1564 ◽

Cited By ~ 19

Author(s):

Hilary Renshaw ◽

José M. Vargas-Muñiz ◽

Amber D. Richards ◽

Yohannes G. Asfaw ◽

Praveen R. Juvvadi ◽

...

Keyword(s):

Aspergillus Fumigatus ◽

Galleria Mellonella ◽

Fungal Growth ◽

Hyphal Growth ◽

Lavage Fluid ◽

Class Ii ◽

Necrosis Factor Alpha ◽

Class V ◽

Content Type ◽

Conidial Viability

Myosins are a family of actin-based motor proteins found in many organisms and are categorized into classes based on their structures. Class II and V myosins are known to be important for critical cellular processes, including cytokinesis, endocytosis, exocytosis, and organelle trafficking, in the model fungiSaccharomyces cerevisiaeandAspergillus nidulans. However, the roles of myosins in the growth and virulence of the pathogenAspergillus fumigatusare unknown. We constructed single- and double-deletion strains of the class II and class V myosins inA. fumigatusand found that while the class II myosin (myoB) is dispensable for growth, the class V myosin (myoE) is required for proper hyphal extension; deletion ofmyoEresulted in hyperbranching and loss of hyphal polarity. BothmyoBandmyoEare necessary for proper septation, conidiation, and conidial germination, but onlymyoBis required for conidial viability. Infection with the ΔmyoEstrain in the invertebrateGalleria mellonellamodel and also in a persistently immunosuppressed murine model of invasive aspergillosis resulted in hypovirulence, while analysis of bronchoalveolar lavage fluid revealed that tumor necrosis factor alpha (TNF-α) release and cellular infiltration were similar compared to those of the wild-type strain. The ΔmyoEstrain showed fungal growth in the murine lung, while the ΔmyoBstrain exhibited little fungal burden, most likely due to the reduced conidial viability. These results show, for the first time, the important role these cytoskeletal components play in the growth of and disease caused by a known pathogen, prompting future studies to understand their regulation and potential targeting for novel antifungal therapies.

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Identification and Characterization of a Novel Aspergillus fumigatus Rhomboid Family Putative Protease, RbdA, Involved in Hypoxia Sensing and Virulence

Infection and Immunity ◽

10.1128/iai.00011-16 ◽

2016 ◽

Vol 84 (6) ◽

pp. 1866-1878 ◽

Cited By ~ 17

Author(s):

Yakir Vaknin ◽

Falk Hillmann ◽

Rossana Iannitti ◽

Netali Ben Baruch ◽

Hana Sandovsky-Losica ◽

...

Keyword(s):

Aspergillus Fumigatus ◽

Regulatory Element ◽

Invasive Pulmonary Aspergillosis ◽

Hyphal Growth ◽

Fungal Virulence ◽

Th17 Response ◽

Content Type ◽

Genes Encoding ◽

Element Binding Protein

Aspergillus fumigatusis the most common pathogenic mold infecting humans and a significant cause of morbidity and mortality in immunocompromised patients. In invasive pulmonary aspergillosis,A. fumigatusspores are inhaled into the lungs, undergoing germination and invasive hyphal growth. The fungus occludes and disrupts the blood vessels, leading to hypoxia and eventual tissue necrosis. The ability of this mold to adapt to hypoxia is regulated in part by the sterol regulatory element binding protein (SREBP) SrbA and the DscA to DscD Golgi E3 ligase complex critical for SREBP activation by proteolytic cleavage. Loss of the genes encoding these proteins results in avirulence. To identify novel regulators of hypoxia sensing, we screened theNeurospora crassagene deletion library under hypoxia and identified a novel rhomboid family protease essential for hypoxic growth. Deletion of theA. fumigatusrhomboid homologrbdAresulted in an inability to grow under hypoxia, hypersensitivity to CoCl2, nikkomycin Z, fluconazole, and ferrozine, abnormal swollen tip morphology, and transcriptional dysregulation—accurately phenocopying deletion ofsrbA. In vivo,rbdAdeletion resulted in increased sensitivity to phagocytic killing, a reduced inflammatory Th1 and Th17 response, and strongly attenuated virulence. Phenotypic rescue of the ΔrbdAmutant was achieved by expression and nuclear localization of the N terminus of SrbA, including its HLH domain, further indicating that RbdA and SrbA act in the same signaling pathway. In summary, we have identified RbdA, a novel putative rhomboid family protease inA. fumigatusthat mediates hypoxia adaptation and fungal virulence and that is likely linked to SrbA cleavage and activation.

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SidL, an Aspergillus fumigatus Transacetylase Involved in Biosynthesis of the Siderophores Ferricrocin and Hydroxyferricrocin

Applied and Environmental Microbiology ◽

10.1128/aem.00182-11 ◽

2011 ◽

Vol 77 (14) ◽

pp. 4959-4966 ◽

Cited By ~ 36

Author(s):

Michael Blatzer ◽

Markus Schrettl ◽

Bettina Sarg ◽

Herbert H. Lindner ◽

Kristian Pfaller ◽

...

Keyword(s):

Aspergillus Fumigatus ◽

Fluorescent Protein ◽

Iron Starvation ◽

Fungal Virulence ◽

Content Type ◽

Siderophore Biosynthesis ◽

Opportunistic Fungal Pathogen ◽

Triacetylfusarinine C ◽

Green Fluorescent ◽

Biosynthetic Machinery

ABSTRACTThe opportunistic fungal pathogenAspergillus fumigatusproduces four types of siderophores, low-molecular-mass iron chelators: it excretes fusarinine C (FsC) and triacetylfusarinine C (TAFC) for iron uptake and accumulates ferricrocin (FC) for hyphal and hydroxyferricrocin (HFC) for conidial iron distribution and storage. Siderophore biosynthesis has recently been shown to be crucial for fungal virulence. Here we identified a new component of the fungal siderophore biosynthetic machinery: AFUA_1G04450, termed SidL. SidL is conserved only in siderophore-producing ascomycetes and shows similarity to transacylases involved in bacterial siderophore biosynthesis and theN5-hydroxyornithine:anhydromevalonyl coenzyme A-N5-transacylase SidF, which is essential for TAFC biosynthesis. Inactivation of SidL inA. fumigatusdecreased FC biosynthesis during iron starvation and completely blocked FC biosynthesis during iron-replete growth. In agreement with these findings, SidL deficiency blocked conidial accumulation of FC-derived HFC under iron-replete conditions, which delayed germination and decreased the size of conidia and their resistance to oxidative stress. Remarkably, thesidLgene is not clustered with other siderophore-biosynthetic genes, and its expression is not affected by iron availability. Tagging of SidL with enhanced green fluorescent protein suggested a cytosolic localization of the FC-biosynthetic machinery. Taken together, these data suggest that SidL is a constitutively activeN5-hydroxyornithine-acetylase required for FC biosynthesis, in particular under iron-replete conditions. Moreover, this study revealed the unexpected complexity of siderophore biosynthesis, indicating the existence of an additional, iron-repressedN5-hydroxyornithine-acetylase.

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