Mitochondrial Complex I Is a Global Regulator of Secondary Metabolism, Virulence and Azole Sensitivity in Fungi

Recent estimates of the global burden of fungal disease suggest that that their incidence has been drastically underestimated and that mortality may rival that of malaria or tuberculosis. Azoles are the principal class of antifungal drug and the only available oral treatment for fungal disease. Rece...

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Main Authors:	Bromley, Mike, Johns, Anna, Davies, Emma, Fraczek, Marcin, Mabey Gilsenan, Jane, Kurbatova, Natalya, Keays, Maria, Kapushesky, Misha, Gut, Marta, Gut, Ivo, Denning, David W., Bowyer, Paul
Format:	Online
Language:	English
Published:	Public Library of Science 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4954691/

id	pubmed-4954691
recordtype	oai_dc
spelling	pubmed-49546912016-08-08 Mitochondrial Complex I Is a Global Regulator of Secondary Metabolism, Virulence and Azole Sensitivity in Fungi Bromley, Mike Johns, Anna Davies, Emma Fraczek, Marcin Mabey Gilsenan, Jane Kurbatova, Natalya Keays, Maria Kapushesky, Misha Gut, Marta Gut, Ivo Denning, David W. Bowyer, Paul Research Article Recent estimates of the global burden of fungal disease suggest that that their incidence has been drastically underestimated and that mortality may rival that of malaria or tuberculosis. Azoles are the principal class of antifungal drug and the only available oral treatment for fungal disease. Recent occurrence and increase in azole resistance is a major concern worldwide. Known azole resistance mechanisms include over—expression of efflux pumps and mutation of the gene encoding the target protein cyp51a, however, for one of the most important fungal pathogens of humans, Aspergillus fumigatus, much of the observed azole resistance does not appear to involve such mechanisms. Here we present evidence that azole resistance in A. fumigatus can arise through mutation of components of mitochondrial complex I. Gene deletions of the 29.9KD subunit of this complex are azole resistant, less virulent and exhibit dysregulation of secondary metabolite gene clusters in a manner analogous to deletion mutants of the secondary metabolism regulator, LaeA. Additionally we observe that a mutation leading to an E180D amino acid change in the 29.9 KD subunit is strongly associated with clinical azole resistant A. fumigatus isolates. Evidence presented in this paper suggests that complex I may play a role in the hypoxic response and that one possible mechanism for cell death during azole treatment is a dysfunctional hypoxic response that may be restored by dysregulation of complex I. Both deletion of the 29.9 KD subunit of complex I and azole treatment alone profoundly change expression of gene clusters involved in secondary metabolism and immunotoxin production raising potential concerns about long term azole therapy. Public Library of Science 2016-07-20 /pmc/articles/PMC4954691/ /pubmed/27438017 http://dx.doi.org/10.1371/journal.pone.0158724 Text en © 2016 Bromley et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Bromley, Mike Johns, Anna Davies, Emma Fraczek, Marcin Mabey Gilsenan, Jane Kurbatova, Natalya Keays, Maria Kapushesky, Misha Gut, Marta Gut, Ivo Denning, David W. Bowyer, Paul
spellingShingle	Bromley, Mike Johns, Anna Davies, Emma Fraczek, Marcin Mabey Gilsenan, Jane Kurbatova, Natalya Keays, Maria Kapushesky, Misha Gut, Marta Gut, Ivo Denning, David W. Bowyer, Paul Mitochondrial Complex I Is a Global Regulator of Secondary Metabolism, Virulence and Azole Sensitivity in Fungi
author_facet	Bromley, Mike Johns, Anna Davies, Emma Fraczek, Marcin Mabey Gilsenan, Jane Kurbatova, Natalya Keays, Maria Kapushesky, Misha Gut, Marta Gut, Ivo Denning, David W. Bowyer, Paul
author_sort	Bromley, Mike
title	Mitochondrial Complex I Is a Global Regulator of Secondary Metabolism, Virulence and Azole Sensitivity in Fungi
title_short	Mitochondrial Complex I Is a Global Regulator of Secondary Metabolism, Virulence and Azole Sensitivity in Fungi
title_full	Mitochondrial Complex I Is a Global Regulator of Secondary Metabolism, Virulence and Azole Sensitivity in Fungi
title_fullStr	Mitochondrial Complex I Is a Global Regulator of Secondary Metabolism, Virulence and Azole Sensitivity in Fungi
title_full_unstemmed	Mitochondrial Complex I Is a Global Regulator of Secondary Metabolism, Virulence and Azole Sensitivity in Fungi
title_sort	mitochondrial complex i is a global regulator of secondary metabolism, virulence and azole sensitivity in fungi
description	Recent estimates of the global burden of fungal disease suggest that that their incidence has been drastically underestimated and that mortality may rival that of malaria or tuberculosis. Azoles are the principal class of antifungal drug and the only available oral treatment for fungal disease. Recent occurrence and increase in azole resistance is a major concern worldwide. Known azole resistance mechanisms include over—expression of efflux pumps and mutation of the gene encoding the target protein cyp51a, however, for one of the most important fungal pathogens of humans, Aspergillus fumigatus, much of the observed azole resistance does not appear to involve such mechanisms. Here we present evidence that azole resistance in A. fumigatus can arise through mutation of components of mitochondrial complex I. Gene deletions of the 29.9KD subunit of this complex are azole resistant, less virulent and exhibit dysregulation of secondary metabolite gene clusters in a manner analogous to deletion mutants of the secondary metabolism regulator, LaeA. Additionally we observe that a mutation leading to an E180D amino acid change in the 29.9 KD subunit is strongly associated with clinical azole resistant A. fumigatus isolates. Evidence presented in this paper suggests that complex I may play a role in the hypoxic response and that one possible mechanism for cell death during azole treatment is a dysfunctional hypoxic response that may be restored by dysregulation of complex I. Both deletion of the 29.9 KD subunit of complex I and azole treatment alone profoundly change expression of gene clusters involved in secondary metabolism and immunotoxin production raising potential concerns about long term azole therapy.
publisher	Public Library of Science
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4954691/
_version_	1613612428379029504

Mitochondrial Complex I Is a Global Regulator of Secondary Metabolism, Virulence and Azole Sensitivity in Fungi

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