title: MIG1 Regulates Resistance of Candida albicans against the Fungistatic Effect of Weak Organic Acids.
abstract: Candida albicans is the leading cause of fungal infections; but it is also a member of the human microbiome, an ecosystem of thousands of microbial species potentially influencing the outcome of host-fungal interactions. Accordingly, antibacterial therapy raises the risk of candidiasis, yet the underlying mechanism is currently not fully understood. We hypothesize the existence of bacterial metabolites that normally control C. albicans growth and of fungal resistance mechanisms against these metabolites. Among the most abundant microbiota-derived metabolites found on human mucosal surfaces are weak organic acids (WOAs), such as acetic, propionic, butyric, and lactic acid. Here, we used quantitative growth assays to investigate the dose-dependent fungistatic properties of WOAs on C. albicans growth and found inhibition of growth to occur at physiologically relevant concentrations and pH values. This effect was conserved across distantly related fungal species both inside and outside the CTG clade. We next screened a library of transcription factor mutants and identified several genes required for the resistance of C. albicans to one or more WOAs. A single gene, MIG1, previously known for its role in glucose repression, conferred resistance against all four acids tested. Consistent with glucose being an upstream activator of Mig1p, the presence of this carbon source was required for WOA resistance in wild-type C. albicans. Conversely, a MIG1-complemented strain completely restored the glucose-dependent resistance against WOAs. We conclude that Mig1p plays a central role in orchestrating a transcriptional program to fight against the fungistatic effect of this class of highly abundant metabolites produced by the gastrointestinal tract microbiota.
authors: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
authors: Fabien
authors: F
authors: Cottier
authors: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
authors: Alrina Shin Min
authors: AS
authors: Tan
authors: Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore.
authors: Xiaoli
authors: X
authors: Xu
authors: Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore.
authors: Yue
authors: Y
authors: Wang
authors: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore norman_pavelka@immunol.a-star.edu.sg.
authors: Norman
authors: http://orcid.org/0000-0003-4542-9970
authors: N
authors: Pavelka
mesh_terms: D019342:Acetic Acid / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D020148:Butyric Acid / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000235:genetics / Q000254:growth & development*; D002177:Candidiasis / Q000382:microbiology; D025141:Drug Resistance, Fungal / Q000235:genetics; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D019344:Lactic Acid / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D011422:Propionates / Q000494:pharmacology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D011422:Propionates; D012097:Repressor Proteins; D020148:Butyric Acid; D019344:Lactic Acid; C029658:propionic acid; D019342:Acetic Acid