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

Jessie MacAlpine, Martin Daniel-Ivad, Zhongle Liu, Junko Yano, Nicole M. Revie, Robert T. Todd, Peter J. Stogios, Hiram Sanchez, Teresa R. O’Meara, Thomas A. Tompkins, Alexei Savchenko, Anna Selmecki, Amanda O. Veri, David R. Andes, Paul L. Fidel, Nicole Robbins, Justin Nodwell, Luke Whitesell and Leah E. Cowen ()
Additional contact information
Jessie MacAlpine: University of Toronto
Martin Daniel-Ivad: University of Toronto
Zhongle Liu: University of Toronto
Junko Yano: Center of Excellence in Oral and Craniofacial Biology, Louisiana State University Health Sciences Center School of Dentistry
Nicole M. Revie: University of Toronto
Robert T. Todd: University of Minnesota Medical School
Peter J. Stogios: University of Toronto
Hiram Sanchez: University of Wisconsin School of Medicine and Public Health
Teresa R. O’Meara: University of Michigan Medical School
Thomas A. Tompkins: Rosell Institute for Microbiome and Probiotics, 6100 Avenue Royalmount
Alexei Savchenko: University of Toronto
Anna Selmecki: University of Minnesota Medical School
Amanda O. Veri: University of Toronto
David R. Andes: University of Wisconsin School of Medicine and Public Health
Paul L. Fidel: Center of Excellence in Oral and Craniofacial Biology, Louisiana State University Health Sciences Center School of Dentistry
Nicole Robbins: University of Toronto
Justin Nodwell: University of Toronto
Luke Whitesell: University of Toronto
Leah E. Cowen: University of Toronto

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26390-w

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