Scedosporium species rank second among the filamentous fungi capable to colonize chronically the respiratory tract of patients with cystic fibrosis (CF). Nevertheless, there is little information on the mechanisms underpinning their virulence. Iron acquisition is critical for the growth and pathogenesis of many bacterial and fungal genera that chronically inhabit the CF lungs. In a previous study, we showed the presence in the genome of Scedosporium apiospermum of several genes relevant for iron uptake, notably SAPIO_CDS2806, an ortholog of sidD, which drives the synthesis of the extracellular hydroxamate-type siderophore fusarinine C (FsC) and its derivative triacetylfusarinine C (TAFC) in Aspergillus fumigatus. Here, we demonstrate that Scedosporium apiospermum sidD gene is required for production of an excreted siderophore, namely, Nα-methylcoprogen B, which also belongs to the hydroxamate family. Blockage of the synthesis of Nα-methylcoprogen B by disruption of the sidD gene resulted in the lack of fungal growth under iron limiting conditions. Still, growth of ΔsidD mutants could be restored by supplementation of the culture medium with a culture filtrate from the parent strain, but not from the mutants. Furthermore, the use of xenosiderophores as the sole source of iron revealed that S. apiospermum can acquire the iron using the hydroxamate siderophores ferrichrome or ferrioxamine, i.e., independently of Nα-methylcoprogen B production. Conversely, Nα-methylcoprogen B is mandatory for iron acquisition from pyoverdine, a mixed catecholate-hydroxamate siderophore. Finally, the deletion of sidD resulted in the loss of virulence in a murine model of scedosporiosis. Our findings demonstrate that S. apiospermum sidD gene drives the synthesis of a unique extracellular, hydroxamate-type iron chelator, which is essential for fungal growth and virulence. This compound scavenges iron from pyoverdine, which might explain why S. apiospermum and Pseudomonas aeruginosa are rarely found simultaneously in the CF lungs.

Groupe d'Etude des Interactions Hôte Pathogène SFR ICAT 4208 Université Angers Université Brest Angers France

Institute of Microbiology of the Czech Academy of Sciences Prague Czechia

Laboratoire de Parasitologie Mycologie Centre Hospitalier Universitaire Angers France

Laboratoire de Parasitologie Mycologie Centre Hospitalier Universitaire Brest France

Unitat de Microbiologia Facultat de Medicina i Ciències de la Salut Universitat Rovira i Virgili and Institut d'Investigació Sanitària Pere Virgili Reus Spain

Zobrazit více v PubMed

Antelo L., Hof C., Welzel K., Eisfeld K., Sterner O., Anke H. (2006). Siderophores produced by PubMed DOI

Bertrand S., Larcher G., Landreau A., Richomme P., Duval O., Bouchara J.-P. (2009). Hydroxamate siderophores of PubMed DOI

Bertrand S., Bouchara J.-P., Venier M.-C., Richomme P., Duval O., Larcher G. (2010). N(α)-methyl coprogen B, a potential marker of the airway colonization by PubMed DOI

Birch L. E., Ruddat M. (2005). Siderophore accumulation and phytopathogenicity in PubMed DOI

Blyth C. C., Middleton P. G., Harun A., Sorrell T. C., Meyer W., Chen S. C.-A. (2010). Clinical associations and prevalence of PubMed DOI

Caza M., Kronstad J. W. (2013). Shared and distinct mechanisms of iron acquisition by bacterial and fungal pathogens of humans. Front. Cell. Infect. Microbiol. 3:80   10.3389/fcimb.2013.00080 PubMed DOI PMC

Chen S. C.-A., Patel S., Meyer W., Chapman B., Yu H., Byth K., et al. (2018). PubMed DOI

Choquer M., Robin G., Le Pêcheur P., Giraud C., Levis C., Viaud M. (2008). Ku70 or Ku80 deficiencies in the fungus PubMed DOI

Donzelli B. G. G., Krasnoff S. B. (2016). “Chapter Ten - Molecular Genetics of Secondary Chemistry in Metarhizium Fungi,” in Advances in Genetics Genetics and Molecular Biology of Entomopathogenic Fungi. Eds. Lovett B, St. Leger R. J. (Cambridge, MA: Academic Press; ), 365–436.   10.1016/bs.adgen.2016.01.005 PubMed DOI

Eichhorn H., Lessing F., Winterberg B., Schirawski J., Kämper J., Müller P., et al. (2006). A ferroxidation/permeation iron uptake system is required for virulence in PubMed DOI PMC

Gandía M., Xu S., Font C., Marcos J. F. (2016). Disruption of PubMed DOI

Gangneux J.-P., Lortholary O., Cornely O. A., Pagano L. (2019). 9th Trends in Medical Mycology held on 11–14 October 2019, Nice, France, organized under the auspices of EORTC-IDG and ECMM. J. Fungi 5, 95.   10.3390/jof5040095 PubMed DOI PMC

Haas H. (2014). Fungal siderophore metabolism with a focus on PubMed DOI PMC

Hissen A. H. T., Chow J. M. T., Pinto L. J., Moore M. M. (2004). Survival of PubMed DOI PMC

Hoff B., Kamerewerd J., Sigl C., Zadra I., Kück U. (2010). Homologous recombination in the antibiotic producer PubMed DOI

Homa M., Sándor A., Tóth E., Szebenyi C., Nagy G., Vágvölgyi C., et al. (2019). In vitro interactions of PubMed DOI PMC

Kaur J., Pethani B. P., Kumar S., Kim M., Sunna A., Kautto L., et al. (2015). PubMed DOI PMC

Krappmann S. (2007). Gene targeting in filamentous fungi: the benefits of impaired repair. Fungal Biol. Rev. 21, 25–29.   10.1016/j.fbr.2007.02.004 DOI

Le Govic Y., Papon N., Le Gal S., Lelièvre B., Bouchara J.-P., Vandeputte P. (2018). Genomic organization and expression of iron metabolism genes in the emerging pathogenic mold PubMed DOI PMC

Le Govic Y., Papon N., Le Gal S., Bouchara J.-P., Vandeputte P. (2019). Non-ribosomal peptide synthetase gene clusters in the human pathogenic fungus PubMed DOI PMC

Li Z.-H., Du C.-M., Zhong Y.-H., Wang T.-H. (2010). Development of a highly efficient gene targeting system allowing rapid genetic manipulations in PubMed DOI

Liu Z., Friesen T. L. (2012). Polyethylene glycol (PEG)-mediated transformation in filamentous fungal pathogens. Methods Mol. Biol. 835, 365–375.   10.1007/978-1-61779-501-5_21 PubMed DOI

Mei B., Budde A. D., Leong S. A. (1993). PubMed DOI PMC

Meyer V. (2008). Genetic engineering of filamentous fungi–progress, obstacles and future trends. Biotechnol. Adv. 26, 177–185.   10.1016/j.biotechadv.2007.12.001 PubMed DOI

Nayak T., Szewczyk E., Oakley C. E., Osmani A., Ukil L., Murray S. L., et al. (2006). A versatile and efficient gene-targeting system for PubMed DOI PMC

Ninomiya Y., Suzuki K., Ishii C., Inoue H. (2004). Highly efficient gene replacements in PubMed DOI PMC

Novák J., Škríba A., Havlíček V. (2020). CycloBranch 2: molecular formula annotations applied to imzML data sets in bimodal fusion and LC-MS data files. Anal. Chem. 92, 6844–6849.   10.1021/acs.analchem.0c00170 PubMed DOI

Oide S., Moeder W., Krasnoff S., Gibson D., Haas H., Yoshioka K., et al. (2006). NPS6, encoding a nonribosomal peptide synthetase involved in siderophore-mediated iron metabolism, is a conserved virulence determinant of plant pathogenic ascomycetes. Plant Cell 18, 2836–2853.   10.1105/tpc.106.045633 PubMed DOI PMC

Pateau V., Razafimandimby B., Vandeputte P., Thornton C. R., Guillemette T., Bouchara J.-P., et al. (2018). Gene disruption in PubMed DOI

Pluháček T., Lemr K., Ghosh D., Milde D., Novák J., Havlíček V. (2016). Characterization of microbial siderophores by mass spectrometry. Mass Spectrom. Rev. 35, 35–47.   10.1002/mas.21461 PubMed DOI

Qi X., Su X., Guo H., Qi J., Cheng H. (2015). A PubMed DOI

Ramanan N., Wang Y. (2000). A high-affinity iron permease essential for PubMed DOI

Ramirez-Garcia A., Pellon A., Rementeria A., Buldain I., Barreto-Bergter E., Rollin-Pinheiro R., et al. (2018). PubMed DOI

Sass G., Nazik H., Penner J., Shah H., Ansari S. R., Clemons K. V., et al. (2018). Studies of PubMed DOI PMC

Sass G., Ansari S. R., Dietl A.-M., Déziel E., Haas H., Stevens D. A. (2019). Intermicrobial interaction: PubMed DOI PMC

Schrettl M., Bignell E., Kragl C., Joechl C., Rogers T., Arst H. N., et al. (2004). Siderophore biosynthesis but not reductive iron assimilation is essential for PubMed DOI PMC

Schrettl M., Bignell E., Kragl C., Sabiha Y., Loss O., Eisendle M., et al. (2007). Distinct roles for intra- and extracellular siderophores during PubMed DOI PMC

Schwarz C., Brandt C., Antweiler E., Krannich A., Staab D., Schmitt-Grohé S., et al. (2017). Prospective multicenter German study on pulmonary colonization with PubMed DOI PMC

Turgeon B. G., Condon B., Liu J., Zhang N. (2010). Protoplast transformation of filamentous fungi. Methods Mol. Biol. 638, 3–19.   10.1007/978-1-60761-611-5_1 PubMed DOI

Waldron K. J., Robinson N. J. (2009). How do bacterial cells ensure that metalloproteins get the correct metal? Nat. Rev. Microbiol. 7, 25–35.   10.1038/nrmicro2057 PubMed DOI

Winkelmann G. (2007). Ecology of siderophores with special reference to the fungi. Biometals 20, 379–392.   10.1007/s10534-006-9076-1 PubMed DOI

Yasmin S., Alcazar-Fuoli L., Gründlinger M., Puempel T., Cairns T., Blatzer M., et al. (2012). Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen PubMed DOI PMC

Exploring the Siderophore Portfolio for Mass Spectrometry-Based Diagnosis of Scedosporiosis and Lomentosporiosis

Current and Future Pathways in Aspergillus Diagnosis