TAC1 Tango: Evolutionary rewiring of a transcriptional circuit for azole drug resistance in Candida auris

Candida auris is an emerging fungal pathogen responsible for multi-drug-resistant infections and persistent
outbreaks in hospitals worldwide. Azole drugs are a cornerstone in the treatment of invasive candidiasis because
of their high oral bioavailability and ease of access even in low-income communities, but high rates of resistance
(~90%) limit their use. Further, outbreaks tend to persist in healthcare settings despite strict sanitation protocols,
and it can tolerate high salt and high temperature conditions that even sister species cannot endure. Together,
these traits are hypothesized to contribute to the near-simultaneous emergence of multiple phylogenetically
distinct lineages around the globe. Understanding how C. auris evolved widespread azole resistance and its
ability to survive environmental stresses is fundamental to improving therapeutic outcomes and assessing
disease threats. Interestingly, the evolutionary history of one transcription factor (TF) is linked to both traits. The
TF regulating sodium pump expression in the related model yeast Saccharomyces cerevisiae, Hal9, evolved to
primarily regulate azole drug pump expression in Candida. In the well-studied Candida albicans, its homolog
Tac1 is the primary mediator of azole resistance via drug pump expression. But the closest Tac1 homolog in C.
auris, Tac1a, is not reported to influence resistance. Instead, Tac1b is a primary mediator of drug resistance.
Preliminary analysis of ~900 C. auris genomes has not identified any TAC1a variants that explain azole
resistance. The proposed work investigates the evolutionary rewiring of this system to attribute these changes
in phenotype to changes in regulatory elements, functions of target genes, or a combination. To determine
changes in regulatory elements, I will map regulatory relationships in azole resistance circuits mediated by Tac1a
and Tac1b using epigenomic and transcriptomic approaches. In C. auris, C. albicans, and S. cerevisiae, I will
delineate the relative contributions of each homolog to drug and salt tolerance. To attribute changes in
phenotypes to changes in target genes, I will characterize evolutionary histories of Candida and clinical C. auris
populations in genes targeted by Tac1 homologs. To predict genes targeted in species without data on
transcriptional regulation, I will train a machine learning model on C. auris gene promoter sequences bound by
Tac1a or Tac1b. To test the hypothesis that the rewiring of circuits identified is an adaptive mechanism, I will
detect accelerated birth-death rates of gene families containing homologs of predicted or known Tac1 targets in
available Candida genomes, and selection on these genes in clinical C. auris populations. The research program
will be performed at Brown University, with access to world-class facilities and interdisciplinary networks across
computational biology, microbiology, and health sciences. Completion of the proposed research, paired with
abundant mentorship, teaching, and outreach opportunities, will build my capacity to launch an independent
program studying emerging fungal pathogens with integrative omics approaches and developing the next
generation of scientists.

Grant Number: 1F32AI194727-01
NIH Institute/Center: NIH
Principal Investigator: Nicholas Cauldron