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.
Bibliographical noteFunding Information:
We thank Merck and Genome Canada for making the original C. albicans DBC and GRACE mutant collections available. We thank all Cowen lab members for helpful discussions. We thank Dr. William Navarre and Erin Wong for the murine gut isolate collection. J.M. was supported by a MITACS fellowship. D.R.A. is supported by a National Institutes of Health (NIH) R01 grant (R01AI073289). A.M.S. is supported by the Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases (No. 1020388) and NIH (R01AI143689). Structural modeling for this work was funded with U.S. Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272201700060C (Center for Structural Genomics of Infectious Diseases) (CSGID). J.N. is supported by a Canadian Institutes of Health Research (CIHR) grant (MOP-133636). L.E.C. is supported by an NSERC Engage grant (EGP 491919-15), the CIHR Foundation grant (FDN-154288), and a NIH R01 grant (R01AI127375); L.E.C. is a Canada Research Chair (Tier 1) in Microbial Genomics & Infectious Disease and coDirector of the CIFAR program, Fungal Kingdom: Threats & Opportunities.
© 2021, The Author(s).