Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus.

Abstract

Aspergillus fumigatus is the most common airborne fungal pathogen for humans. In this mold, iron starvation induces production of the siderophore triacetylfusarinine C (TAFC). Here we demonstrate a link between TAFC and ergosterol biosynthetic pathways, which are both critical for virulence and treatment of fungal infections. Consistent with mevalonate being a limiting prerequisite for TAFC biosynthesis, we observed increased expression of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase (Hmg1) under iron starvation, reduced TAFC biosynthesis following lovastatin-mediated Hmg1 inhibition, and increased TAFC biosynthesis following Hmg1 overexpression. We identified enzymes, the acyl-CoA ligase SidI and the enoyl-CoA hydratase SidH, linking biosynthesis of mevalonate and TAFC, deficiency of which under iron starvation impaired TAFC biosynthesis, growth, oxidative stress resistance, and murine virulence. Moreover, inactivation of these enzymes alleviated TAFC-derived biosynthetic demand for mevalonate, as evidenced by increased resistance to lovastatin. Concordant with bilateral demand for mevalonate, iron starvation decreased the ergosterol content and composition, a phenotype that is mitigated in TAFC-lacking mutants.

• Authors: Sabiha Yasmin, Laura Alcazar-Fuoli, Mario Gründlinger, Thomas Puempel, Timothy Cairns, Michael Blatzer, Jordi F Lopez, Joan O Grimalt, Elaine Bignell, Hubertus Haas
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 8 Pg. E497-504 (Feb 21 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 22106303 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ferric Compounds
• Hydroxamic Acids
• Pyrimidines
• Siderophores
• Triazoles
• N,N',N''-triacetylfusarinine C
• Amphotericin B
• Lovastatin
• Hydroxymethylglutaryl CoA Reductases
• Enoyl-CoA Hydratase
• Ligases
• Voriconazole
• Mevalonic Acid
• Ergosterol

Topics

• Amphotericin B (pharmacology)
• Animals
• Aspergillus fumigatus (enzymology, genetics, metabolism, pathogenicity)
• Biomass
• Biosynthetic Pathways (drug effects)
• Enoyl-CoA Hydratase (metabolism)
• Ergosterol (biosynthesis)
• Ferric Compounds (metabolism)
• Gene Deletion
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Fungal (drug effects)
• Gene Silencing (drug effects)
• Genes, Fungal (genetics)
• Hydroxamic Acids (metabolism)
• Hydroxymethylglutaryl CoA Reductases (genetics, metabolism)
• Iron Deficiencies
• Ligases (metabolism)
• Lovastatin (pharmacology)
• Mevalonic Acid (metabolism)
• Mice
• Microbial Sensitivity Tests
• Oxidative Stress (drug effects)
• Pulmonary Aspergillosis (microbiology)
• Pyrimidines (pharmacology)
• Siderophores (biosynthesis)
• Triazoles (pharmacology)
• Up-Regulation (drug effects)
• Virulence (drug effects, genetics)
• Voriconazole