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Targeting methionine synthase in a fungal pathogen causes a metabolic imbalance that impacts cell energetics, growth and virulence

ABSTRACT: There is an urgent need to develop novel antifungals to tackle the threat that fungal pathogens pose to human health. In this work, we have performed a thorough characterisation and validation of the promising target methionine synthase. We have uncovered that in Aspergillus fumigatus the absence of its enzymatic activity triggers a metabolic imbalance that causes a reduction in intracellular ATP. This drop in cell energetics prevents fungal growth, even in the presence of methionine. Using a tetOFF genetic model to mimic drug treatment we show that repression of methionine synthase in growing hyphae halts growth in vitro, which translates into a beneficial effect in vivo when targeting established infections. Finally, a structural-based virtual screening of methionine synthases reveals key differences between the human and fungal structures and unravels particularities of the fungal pockets that can direct the design of novel specific and broad-spectrum inhibitors. Therefore, methionine synthase is a valuable target for the development of new antifungals.

INSTRUMENT(S): Gas Chromatography MS -

SUBMITTER: Howbeer Muhamadali

PROVIDER: MTBLS1636 | MetaboLights | 2020-10-15

REPOSITORIES: MetaboLights

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			Action	DRS
	MTBLS1636	Other
	FILES	Other
	a_MTBLS1636_GC-MS___metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS1636_GC-MS___metabolite_profiling_v2_maf.tsv	Tabular

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Project description:In this study, we combined metabolic reconstruction, growth assays, metabolome and transcriptome analyses to obtain a global view of the sulfur metabolic network and of the response to sulfur availability in Brevibacterium aurantiacum. In agreement with the growth of B. aurantiacum in the presence of sulfate and cystine, the metabolic reconstruction showed the presence of a sulfate assimilation pathway and of thiolation pathways that produce cysteine (cysE and cysK) or homocysteine (metX and metY) from sulfide, of at least one gene of the transsulfuration pathway (aecD) and of genes encoding three MetE-type methionine synthases. We also compared the expression profiles of B. aurantiacum ATCC9175 during sulfur starvation and in the presence of sulfate, cystine or methionine plus cystine. In sulfur starvation, 690 genes including 21 genes involved in sulfur metabolism and 29 genes encoding amino acids and peptide transporters were differentially expressed. We also investigated changes in pools of sulfur-containing metabolites and in expression profiles after growth in the presence of sulfate, cystine or methionine plus cystine. The expression of genes involved in sulfate assimilation and cysteine synthesis was repressed in presence of cysteine, while the expression of metX, metY, metE1, metE2 and BL613 encoding a probable cystathionine-γ-synthase decreased in the presence of methionine. We identified three ABC transporters: two stronger transcribed during cysteine limitation and one during methionine depletion. Finally, the expression of genes encoding a methionine γ-lyase, BL929, and a methionine transporter (metPS) was induced in the presence of methionine, in conjunction with a significant increase of volatile sulfur compounds production. Refer to individual Series. This SuperSeries is composed of the following subset Series: GSE25418: BA-Methionine plus Cystine vs Cystine GSE25419: BA-Sulfate vs Cystine GSE25420: BA-Methionine plus Cystine vs Sulfate GSE25421: BA-Sulfate vs Sulfate starvation

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Targeting methionine synthase in a fungal pathogen causes a metabolic imbalance that impacts cell energetics, growth and virulence

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