@article{938098d04a0547f8a182d2a7a4ace010,
title = "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. In this work, we have performed a comprehensive characterisation and validation of the promising target methionine synthase (MetH). We uncover 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 evidences 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 structural-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.",
keywords = "Antifungal target, Aspergillus fumigatus, Doxycycline, Established infection, Fungal virulence, Methionine synthase, Primary metabolism, Target validation, TetOFF",
author = "Jennifer Scott and {Sueiro Olivares}, Monica and Benjamin Thornton and Owens, {Rebecca A} and Howbeer Muhamadali and Rachael Fortune-Grant and Darren Thomson and Riba Thomas and Katherine Hollywood and Sean Doyle and Royston Goodacre and Lydia Tabernero and Elaine Bignell and {Amich Elias}, Jorge",
note = "Funding Information: J.A. was supported by a MRC Career Development Award (MR/N008707/1). J.S. was supported by a BSAC scholarship (bsac-2016-0049). B.P.T. was supported by a MRC Doctoral Training Partnership PhD studentship. Q-Exactive mass spectrometer and nanoLC instrumentation were funded by a competitive infrastructure award from Science Foundation Ireland [12/RI/2346(3)]. Publisher Copyright: {\textcopyright} 2020 Scott et al. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",
year = "2020",
month = oct,
day = "13",
doi = "10.1128/mBio.01985-20",
language = "English",
volume = "11",
pages = "1--23",
journal = "mBio",
issn = "2161-2129",
publisher = "American Society for Microbiology",
number = "5",
}