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 fungal pathogens pose to human health. Here, we have performed a comprehensive characterization and validation of the promising target methionine synthase (MetH). We show that in Aspergillus fumigatus the absence of t...

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Autores principales:	Jennifer Scott, Monica Sueiro-Olivares, Benjamin P. Thornton, Rebecca A. Owens, Howbeer Muhamadali, Rachael Fortune-Grant, Darren Thomson, Riba Thomas, Katherine Hollywood, Sean Doyle, Royston Goodacre, Lydia Tabernero, Elaine Bignell, Jorge Amich
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	antifungal target Aspergillus fumigatus doxycycline established infection fungal virulence methionine synthase Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7b12c5539a3341cab8baab5ee44d445b
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spelling	oai:doaj.org-article:7b12c5539a3341cab8baab5ee44d445b2021-11-15T16:19:09ZTargeting Methionine Synthase in a Fungal Pathogen Causes a Metabolic Imbalance That Impacts Cell Energetics, Growth, and Virulence10.1128/mBio.01985-202150-7511https://doaj.org/article/7b12c5539a3341cab8baab5ee44d445b2020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01985-20https://doaj.org/toc/2150-7511ABSTRACT There is an urgent need to develop novel antifungals to tackle the threat fungal pathogens pose to human health. Here, we have performed a comprehensive characterization and validation of the promising target methionine synthase (MetH). We show that in Aspergillus fumigatus the absence of this enzymatic activity triggers a metabolic imbalance that causes a reduction in intracellular ATP, which prevents fungal growth even in the presence of methionine. Interestingly, growth can be recovered in the presence of certain metabolites, which shows that metH is a conditionally essential gene and consequently should be targeted in established infections for a more comprehensive validation. Accordingly, we have validated the use of the tetOFF genetic model in fungal research and improved its performance in vivo to achieve initial validation of targets in models of established infection. We show that repression of metH in growing hyphae halts growth in vitro, which translates into a beneficial effect when targeting established infections using this model in vivo. Finally, a structure-based virtual screening of methionine synthases reveals key differences between the human and fungal structures and unravels features in the fungal enzyme that can guide the design of novel specific inhibitors. Therefore, methionine synthase is a valuable target for the development of new antifungals. IMPORTANCE Fungal pathogens are responsible for millions of life-threatening infections on an annual basis worldwide. The current repertoire of antifungal drugs is very limited and, worryingly, resistance has emerged and already become a serious threat to our capacity to treat fungal diseases. The first step to develop new drugs is often to identify molecular targets in the pathogen whose inhibition during infection can prevent its growth. However, the current models are not suitable to validate targets in established infections. Here, we have characterized the promising antifungal target methionine synthase in great detail, using the prominent fungal pathogen Aspergillus fumigatus as a model. We have uncovered the underlying reason for its essentiality and confirmed its druggability. Furthermore, we have optimized the use of a genetic system to show a beneficial effect of targeting methionine synthase in established infections. Therefore, we believe that antifungal drugs to target methionine synthase should be pursued and additionally, we provide a model that permits gaining information about the validity of antifungal targets in established infections.Jennifer ScottMonica Sueiro-OlivaresBenjamin P. ThorntonRebecca A. OwensHowbeer MuhamadaliRachael Fortune-GrantDarren ThomsonRiba ThomasKatherine HollywoodSean DoyleRoyston GoodacreLydia TaberneroElaine BignellJorge AmichAmerican Society for Microbiologyarticleantifungal targetAspergillus fumigatusdoxycyclineestablished infectionfungal virulencemethionine synthaseMicrobiologyQR1-502ENmBio, Vol 11, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	antifungal target Aspergillus fumigatus doxycycline established infection fungal virulence methionine synthase Microbiology QR1-502
spellingShingle	antifungal target Aspergillus fumigatus doxycycline established infection fungal virulence methionine synthase Microbiology QR1-502 Jennifer Scott Monica Sueiro-Olivares Benjamin P. Thornton Rebecca A. Owens Howbeer Muhamadali Rachael Fortune-Grant Darren Thomson Riba Thomas Katherine Hollywood Sean Doyle Royston Goodacre Lydia Tabernero Elaine Bignell Jorge Amich Targeting Methionine Synthase in a Fungal Pathogen Causes a Metabolic Imbalance That Impacts Cell Energetics, Growth, and Virulence
description	ABSTRACT There is an urgent need to develop novel antifungals to tackle the threat fungal pathogens pose to human health. Here, we have performed a comprehensive characterization and validation of the promising target methionine synthase (MetH). We show that in Aspergillus fumigatus the absence of this enzymatic activity triggers a metabolic imbalance that causes a reduction in intracellular ATP, which prevents fungal growth even in the presence of methionine. Interestingly, growth can be recovered in the presence of certain metabolites, which shows that metH is a conditionally essential gene and consequently should be targeted in established infections for a more comprehensive validation. Accordingly, we have validated the use of the tetOFF genetic model in fungal research and improved its performance in vivo to achieve initial validation of targets in models of established infection. We show that repression of metH in growing hyphae halts growth in vitro, which translates into a beneficial effect when targeting established infections using this model in vivo. Finally, a structure-based virtual screening of methionine synthases reveals key differences between the human and fungal structures and unravels features in the fungal enzyme that can guide the design of novel specific inhibitors. Therefore, methionine synthase is a valuable target for the development of new antifungals. IMPORTANCE Fungal pathogens are responsible for millions of life-threatening infections on an annual basis worldwide. The current repertoire of antifungal drugs is very limited and, worryingly, resistance has emerged and already become a serious threat to our capacity to treat fungal diseases. The first step to develop new drugs is often to identify molecular targets in the pathogen whose inhibition during infection can prevent its growth. However, the current models are not suitable to validate targets in established infections. Here, we have characterized the promising antifungal target methionine synthase in great detail, using the prominent fungal pathogen Aspergillus fumigatus as a model. We have uncovered the underlying reason for its essentiality and confirmed its druggability. Furthermore, we have optimized the use of a genetic system to show a beneficial effect of targeting methionine synthase in established infections. Therefore, we believe that antifungal drugs to target methionine synthase should be pursued and additionally, we provide a model that permits gaining information about the validity of antifungal targets in established infections.
format	article
author	Jennifer Scott Monica Sueiro-Olivares Benjamin P. Thornton Rebecca A. Owens Howbeer Muhamadali Rachael Fortune-Grant Darren Thomson Riba Thomas Katherine Hollywood Sean Doyle Royston Goodacre Lydia Tabernero Elaine Bignell Jorge Amich
author_facet	Jennifer Scott Monica Sueiro-Olivares Benjamin P. Thornton Rebecca A. Owens Howbeer Muhamadali Rachael Fortune-Grant Darren Thomson Riba Thomas Katherine Hollywood Sean Doyle Royston Goodacre Lydia Tabernero Elaine Bignell Jorge Amich
author_sort	Jennifer Scott
title	Targeting Methionine Synthase in a Fungal Pathogen Causes a Metabolic Imbalance That Impacts Cell Energetics, Growth, and Virulence
title_short	Targeting Methionine Synthase in a Fungal Pathogen Causes a Metabolic Imbalance That Impacts Cell Energetics, Growth, and Virulence
title_full	Targeting Methionine Synthase in a Fungal Pathogen Causes a Metabolic Imbalance That Impacts Cell Energetics, Growth, and Virulence
title_fullStr	Targeting Methionine Synthase in a Fungal Pathogen Causes a Metabolic Imbalance That Impacts Cell Energetics, Growth, and Virulence
title_full_unstemmed	Targeting Methionine Synthase in a Fungal Pathogen Causes a Metabolic Imbalance That Impacts Cell Energetics, Growth, and Virulence
title_sort	targeting methionine synthase in a fungal pathogen causes a metabolic imbalance that impacts cell energetics, growth, and virulence
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/7b12c5539a3341cab8baab5ee44d445b
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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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