A small molecule produced by Lactobacillus species blocks Candida albicans filamentation by inhibiting a DYRK1-family kinase.

Animals Antifungal Agents / metabolism Biofilms / drug effects Candida albicans / drug effects Candidiasis / microbiology Carbolines / metabolism Drug Resistance, Fungal / genetics Fungal Proteins / genetics Hyphae / drug effects Lactobacillus / metabolism Mutation Protein Kinase Inhibitors / metabolism Protein Serine-Threonine Kinases / antagonists & inhibitors Protein-Tyrosine Kinases / antagonists & inhibitors Rats Virulence / drug effects Dyrk Kinases

Journal

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

Informations de publication

Date de publication:
22 10 2021
Historique:
received: 06 08 2021
accepted: 01 10 2021
entrez: 23 10 2021
pubmed: 24 10 2021
medline: 15 12 2021
Statut: epublish

Résumé

The fungus Candida albicans is an opportunistic pathogen that can exploit imbalances in microbiome composition to invade its human host, causing pathologies ranging from vaginal candidiasis to fungal sepsis. Bacteria of the genus Lactobacillus are colonizers of human mucosa and can produce compounds with bioactivity against C. albicans. Here, we show that some Lactobacillus species produce a small molecule under laboratory conditions that blocks the C. albicans yeast-to-filament transition, an important virulence trait. It remains unexplored whether the compound is produced in the context of the human host. Bioassay-guided fractionation of Lactobacillus-conditioned medium linked this activity to 1-acetyl-β-carboline (1-ABC). We use genetic approaches to show that filamentation inhibition by 1-ABC requires Yak1, a DYRK1-family kinase. Additional biochemical characterization of structurally related 1-ethoxycarbonyl-β-carboline confirms that it inhibits Yak1 and blocks C. albicans biofilm formation. Thus, our findings reveal Lactobacillus-produced 1-ABC can prevent the yeast-to-filament transition in C. albicans through inhibition of Yak1.

Identifiants

DOI: 10.1038/s41467-021-26390-w PMID: 34686660 PMC: PMC8536679
pubmed: 34686660
doi: 10.1038/s41467-021-26390-w
pii: 10.1038/s41467-021-26390-w
pmc: PMC8536679
doi:

Substances chimiques

Antifungal Agents 0
Carbolines 0
Fungal Proteins 0
Protein Kinase Inhibitors 0
Protein-Tyrosine Kinases EC 2.7.10.1
Protein Serine-Threonine Kinases EC 2.7.11.1

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

6151

Subventions

Organisme : CIHR
ID : MOP-133636
Pays : Canada
Organisme : NIAID NIH HHS
ID : R01 AI143689
Pays : United States
Organisme : NIGMS NIH HHS
ID : U54 GM104940
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI127375
Pays : United States
Organisme : CIHR
ID : FDN-154288
Pays : Canada
Organisme : NIAID NIH HHS
ID : HHSN272201700060C
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI073289
Pays : United States

Informations de copyright

© 2021. The Author(s).

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Auteurs

Jessie MacAlpine (J)

Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.

Martin Daniel-Ivad (M)

Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
ORCID: 0000-0001-6747-660X

Zhongle Liu (Z)

Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.

Junko Yano (J)

Center of Excellence in Oral and Craniofacial Biology, Louisiana State University Health Sciences Center School of Dentistry, New Orleans, LA, USA.

Nicole M Revie (NM)

Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.

Robert T Todd (RT)

Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA.

Peter J Stogios (PJ)

BioZone, Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada.
Center for Structural Genomics of Infectious Diseases (CSGID), Chicago, IL, USA.

Hiram Sanchez (H)

Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI, USA.
ORCID: 0000-0002-6286-650X

Teresa R O'Meara (TR)

Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
ORCID: 0000-0002-8901-0154

Thomas A Tompkins (TA)

Rosell Institute for Microbiome and Probiotics, 6100 Avenue Royalmount, Montreal, QC, Canada.
ORCID: 0000-0002-2990-2265

Alexei Savchenko (A)

BioZone, Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada.
Center for Structural Genomics of Infectious Diseases (CSGID), Chicago, IL, USA.
Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB, Canada.

Anna Selmecki (A)

Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA.

Amanda O Veri (AO)

Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.

David R Andes (DR)

Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI, USA.
ORCID: 0000-0002-7927-9950

Paul L Fidel (PL)

Center of Excellence in Oral and Craniofacial Biology, Louisiana State University Health Sciences Center School of Dentistry, New Orleans, LA, USA.

Nicole Robbins (N)

Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.

Justin Nodwell (J)

Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
ORCID: 0000-0001-7909-1803

Luke Whitesell (L)

Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
ORCID: 0000-0001-6445-5766

Leah E Cowen (LE)

Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. leah.cowen@utoronto.ca.
ORCID: 0000-0001-5797-0110

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › A small molecule produced by Lactobacillus...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antifongiques › A small molecule produced by Lactobacillus...
questionsmedicales.fr › Phénomènes microbiologiques › Biofilms › A small molecule produced by Lactobacillus...
questionsmedicales.fr › Eucaryotes › Champignons › Levures › Candida › Candida albicans › A small molecule produced by Lactobacillus...
questionsmedicales.fr › Infection › Infections bactériennes et mycoses › Mycoses › Candidose › A small molecule produced by Lactobacillus...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérocycliques 3 noyaux › Carbolines › A small molecule produced by Lactobacillus...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance microbienne aux médicaments › Résistance des champignons aux médicaments › A small molecule produced by Lactobacillus...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines fongiques › A small molecule produced by Lactobacillus...
questionsmedicales.fr › Structures fongiques › Mycelium › Hyphae › A small molecule produced by Lactobacillus...
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