The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus.

Amphotericin B / pharmacology Antifungal Agents / pharmacology Aspergillus fumigatus / drug effects Azoles / pharmacology Drug Resistance, Fungal Fungal Proteins / genetics Microbial Sensitivity Tests

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
22 01 2020
Historique:
received: 02 07 2019
accepted: 13 12 2019
entrez: 24 1 2020
pubmed: 24 1 2020
medline: 14 4 2020
Statut: epublish

Résumé

The frequency of antifungal resistance, particularly to the azole class of ergosterol biosynthetic inhibitors, is a growing global health problem. Survival rates for those infected with resistant isolates are exceptionally low. Beyond modification of the drug target, our understanding of the molecular basis of azole resistance in the fungal pathogen Aspergillus fumigatus is limited. We reasoned that clinically relevant antifungal resistance could derive from transcriptional rewiring, promoting drug resistance without concomitant reductions in pathogenicity. Here we report a genome-wide annotation of transcriptional regulators in A. fumigatus and construction of a library of 484 transcription factor null mutants. We identify 12 regulators that have a demonstrable role in itraconazole susceptibility and show that loss of the negative cofactor 2 complex leads to resistance, not only to the azoles but also the salvage therapeutics amphotericin B and terbinafine without significantly affecting pathogenicity.

Identifiants

DOI: 10.1038/s41467-019-14191-1 PMID: 31969561 PMC: PMC7194077
pubmed: 31969561
doi: 10.1038/s41467-019-14191-1
pii: 10.1038/s41467-019-14191-1
pmc: PMC7194077
doi:

Substances chimiques

Antifungal Agents 0
Azoles 0
Fungal Proteins 0
Amphotericin B 7XU7A7DROE

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

427

Subventions

Organisme : NIAID NIH HHS
ID : R01 AI130128
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI081838
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI143198
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M02010X/1
Pays : United Kingdom

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Auteurs

Takanori Furukawa (T)

Manchester Fungal Infection Group, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, CTF Building, 46 Grafton Street, Manchester, M13 9NT, UK.
Lydia Becker Institute of Immunology and Inflammation, Manchester Collaborative Centre for Inflammation Research, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
ORCID: 0000-0001-9385-9612

Norman van Rhijn (N)

Manchester Fungal Infection Group, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, CTF Building, 46 Grafton Street, Manchester, M13 9NT, UK.
Lydia Becker Institute of Immunology and Inflammation, Manchester Collaborative Centre for Inflammation Research, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
ORCID: 0000-0001-6722-2757

Marcin Fraczek (M)

Manchester Fungal Infection Group, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, CTF Building, 46 Grafton Street, Manchester, M13 9NT, UK.

Fabio Gsaller (F)

Manchester Fungal Infection Group, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, CTF Building, 46 Grafton Street, Manchester, M13 9NT, UK.

Emma Davies (E)

Manchester Fungal Infection Group, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, CTF Building, 46 Grafton Street, Manchester, M13 9NT, UK.

Paul Carr (P)

Manchester Fungal Infection Group, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, CTF Building, 46 Grafton Street, Manchester, M13 9NT, UK.

Sara Gago (S)

Manchester Fungal Infection Group, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, CTF Building, 46 Grafton Street, Manchester, M13 9NT, UK.
Lydia Becker Institute of Immunology and Inflammation, Manchester Collaborative Centre for Inflammation Research, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
ORCID: 0000-0002-7027-4598

Rachael Fortune-Grant (R)

Manchester Fungal Infection Group, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, CTF Building, 46 Grafton Street, Manchester, M13 9NT, UK.
Lydia Becker Institute of Immunology and Inflammation, Manchester Collaborative Centre for Inflammation Research, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

Sayema Rahman (S)

Manchester Fungal Infection Group, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, CTF Building, 46 Grafton Street, Manchester, M13 9NT, UK.
Lydia Becker Institute of Immunology and Inflammation, Manchester Collaborative Centre for Inflammation Research, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

Jane Mabey Gilsenan (JM)

Manchester Fungal Infection Group, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, CTF Building, 46 Grafton Street, Manchester, M13 9NT, UK.

Emma Houlder (E)

Lydia Becker Institute of Immunology and Inflammation, Manchester Collaborative Centre for Inflammation Research, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
ORCID: 0000-0003-0448-6055

Caitlin H Kowalski (CH)

Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, 03766, USA.

Shriya Raj (S)

Unité des Aspergillus, Institut Pasteur, 25 rue du Docteur Roux, 75724 Cedex 15, Paris, France.
ORCID: 0000-0002-1973-6347

Sanjoy Paul (S)

Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA.

Peter Cook (P)

Lydia Becker Institute of Immunology and Inflammation, Manchester Collaborative Centre for Inflammation Research, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
ORCID: 0000-0002-5208-4985

Josie E Parker (JE)

Institute of Life Science, Swansea University Medical School, Swansea University, Swansea, Wales, SA2 8PP, UK.
ORCID: 0000-0002-3855-4194

Steve Kelly (S)

Institute of Life Science, Swansea University Medical School, Swansea University, Swansea, Wales, SA2 8PP, UK.
ORCID: 0000-0001-7991-5040

Robert A Cramer (RA)

Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, 03766, USA.

Jean-Paul Latgé (JP)

Unité des Aspergillus, Institut Pasteur, 25 rue du Docteur Roux, 75724 Cedex 15, Paris, France.

Scott Moye-Rowley (S)

Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA.

Elaine Bignell (E)

Manchester Fungal Infection Group, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, CTF Building, 46 Grafton Street, Manchester, M13 9NT, UK.
Lydia Becker Institute of Immunology and Inflammation, Manchester Collaborative Centre for Inflammation Research, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

Paul Bowyer (P)

Manchester Fungal Infection Group, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, CTF Building, 46 Grafton Street, Manchester, M13 9NT, UK. Paul.Bowyer@manchester.ac.uk.
Lydia Becker Institute of Immunology and Inflammation, Manchester Collaborative Centre for Inflammation Research, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. Paul.Bowyer@manchester.ac.uk.

Michael J Bromley (MJ)

Manchester Fungal Infection Group, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, CTF Building, 46 Grafton Street, Manchester, M13 9NT, UK. Mike.Bromley@manchester.ac.uk.
Lydia Becker Institute of Immunology and Inflammation, Manchester Collaborative Centre for Inflammation Research, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. Mike.Bromley@manchester.ac.uk.
ORCID: 0000-0002-7611-0201

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Classifications MeSH

questionsmedicales.fr › Composés chimiques organiques › Lactones › Amphotéricine B › The negative cofactor 2 complex is a key...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antifongiques › The negative cofactor 2 complex is a key...
questionsmedicales.fr › Eucaryotes › Champignons › Deuteromycota › Aspergillus › Aspergillus fumigatus › The negative cofactor 2 complex is a key...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azoles › The negative cofactor 2 complex is a key...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance microbienne aux médicaments › Résistance des champignons aux médicaments › The negative cofactor 2 complex is a key...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines fongiques › The negative cofactor 2 complex is a key...
questionsmedicales.fr › Techniques d'investigation › Évaluation préclinique de médicament › Tests de sensibilité microbienne › The negative cofactor 2 complex is a key...