title: Interface of Candida albicans biofilm matrix-associated drug resistance and cell wall integrity regulation.
abstract: Candida albicans frequently infects medical devices by growing as a biofilm, i.e., a community of adherent organisms entrenched in an extracellular matrix. During biofilm growth, Candida spp. acquire the ability to resist high concentrations of antifungal drugs. One recently recognized biofilm resistance mechanism involves drug sequestration by matrix β-1,3 glucan. Using a candidate gene approach, we investigated potential C. albicans β-1,3-glucan regulators, based on their homology to Saccharomyces cerevisiae, including SMI1 and protein kinase C (PKC) pathway components. We identified a role for the SMI1 in biofilm matrix glucan production and development of the associated drug resistance phenotype. This pathway appears to act through transcription factor Rlmp and glucan synthase Fks1p. The phenotypes of these mutant biofilms mimicked those of the smi1Δ/smi1Δ biofilm, and overexpression of FKS1 in the smi1Δ/smi1Δ mutant restored the biofilm resistant phenotype. However, control of this pathway is distinct from that of the upstream PKC pathway because the pkc1Δ/pkc1Δ, bck1Δ/bck1Δ, mkk2Δ/mkk2Δ, and mkc1Δ/mkc1Δ biofilms retained the resistant phenotype of the parent strain. In addition, resistance to cell-perturbing agents and gene expression data do not support a significant role for the cell wall integrity pathway during the biofilm formation. Here we show that Smi1p functions in conjunction with Rlm1p and Fks1p to produce drug-sequestering biofilm β-glucan. Our work provides new insight into how the C. albicans biofilm matrix production and drug resistance pathways intersect with the planktonic cell wall integrity pathway. This novel connection helps explain how pathogens in a multicellular biofilm community are protected from anti-infective therapy.
authors.affiliation: University of Wisconsin, Department of Medicine, Madison, WI 53705, USA.
authors.forename: Jeniel E
authors.initials: JE
authors.lastname: Nett
authors.forename: Hiram
authors.initials: H
authors.lastname: Sanchez
authors.forename: Michael T
authors.initials: MT
authors.lastname: Cain
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Ross
authors.forename: David R
authors.initials: DR
authors.lastname: Andes
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use; D018441:Biofilms; D002176:Candida albicans / Q000187:drug effects / Q000378:metabolism / Q000472:pathogenicity / Q000502:physiology*; D002177:Candidiasis / Q000188:drug therapy; D057785:Catheters / Q000382:microbiology; D002473:Cell Wall / Q000378:metabolism* / Q000648:ultrastructure; D025141:Drug Resistance, Fungal; D015725:Fluconazole / Q000494:pharmacology / Q000627:therapeutic use; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D055786:Gene Knockout Techniques; D005964:Glucosyltransferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014774:Virulence; D047071:beta-Glucans / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D047071:beta-Glucans; D015725:Fluconazole; D005964:Glucosyltransferases; C040232:glucan synthase; D011493:Protein Kinase C