Abstract
Mucorales are fungi with increasing importance in the clinics. Infections take a rapidly progressive course resulting in high mortality rates. The ergosterol biosynthesis pathway and sterol composition are of interest, since they are targeted by currently applied antifungal drugs. Nevertheless, Mucorales often exhibit resistance to these drugs, resulting in therapeutic failure. Here, sterol patterns of six clinically relevant Mucorales (Lichtheimia corymbifera, Lichtheimia ramosa, Mucor circinelloides, Rhizomucor pusillus, Rhizopus arrhizus, and Rhizopus microsporus) were analysed in a targeted metabolomics fashion after derivatization by gas chromatography-mass spectrometry. Additionally, the effect of posaconazole (POS) treatment on the sterol pattern of R. arrhizus was evaluated. Overall, fifteen different sterols were detected with species dependent variations in the total and relative sterol amount. Sterol analysis from R. arrhizus hyphae confronted with sublethal concentrations of posaconazole revealed the accumulation of 14-methylergosta-8,24-diene-3,6-diol, which is a toxic sterol that was previously only detected in yeasts. Sterol content and composition were further compared to the well-characterized pathogenic mold Aspergillus fumigatus. This work contributes to a better understanding of the ergosterol biosynthesis pathway of Mucorales, which is essential to improve antifungal efficacy, the identification of targets for novel drug design, and to investigate the combinatorial effects of drugs targeting this pathway.
Highlights
The order Mucorales represent the most prominent order of zygospore-forming fungi, which was formerly placed in the phylum Zygomycota and was referred to as Zygomycetes
amphotericin B (AMB) forms 1:1 adducts approved by the Food and Drug Administration (FDA) as a stand‐alone treatment for mucormycosis with fungal ergosterol and induces an accumulation of reactive oxygen species in the cytoplasm [14,15]
As drugs the target of the currentlyisused antifungal against respectively, it is of great importance to understand the biosynthetic pathway and decipher the Mucorales is ergosterol or its biosynthesis, respectively, it is of great importance to understand the differences to other human pathogenic fungi
Summary
The order Mucorales represent the most prominent order of zygospore-forming fungi, which was formerly placed in the phylum Zygomycota and was referred to as Zygomycetes. AMB forms 1:1 adducts approved by the Food and Drug Administration (FDA) as a stand‐alone treatment for mucormycosis with fungal ergosterol and induces an accumulation of reactive oxygen species in the cytoplasm [14,15]. AMB forms 1:1 adducts with fungal ergosterol and induces an accumulation of reactive Azoles their inhibiting thetheir enzyme sterol C14-demethylase As drugs the target of the currentlyisused antifungal against respectively, it is of great importance to understand the biosynthetic pathway and decipher the Mucorales is ergosterol or its biosynthesis, respectively, it is of great importance to understand the differences to other human pathogenic fungi. For two major in human pathogenic fungi, the yeast Candida albicans, the mold fumigatus, differences the ergosterol biosynthesis pathways have already beenand elucidated. The obtained data were compared to the well-studied ergosterol biosynthetic pathway of Aspergillus fumigatus [16,24,25,27,30,40,41,42,43,44,45,46]
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