June 10, 2022
Candida glabrata and Saccharomyces cerevisiae are closely related yeasts of which the former is pathogenic to mammals and the latter is used to make bread, wine, and beer. At present, the ~400,000 annual cases of life-threatening Candida infection are at risk of increase due to multidrug-resistant strains. Fungal drug resistance relies on the fungal-specific pleiotropic drug resistance (PDR) pathway, in which ATP is consumed to pump drugs out of cells. The PDR pathway is similar among related fungi and a recent study by Nikolov et al. in Nature Communications leveraged this similarity to delve further into genetic regulation of PDR drug resistance in the tractable and benign S. cerevisiae. The team then applied these findings to the virulent C. glabrata.
In S. cerevisiae, the genes involved in PDR share a common promoter element called the PDR responsive element (PDRE). Nikolov et al. discovered that the histone chaperone Rtt106p has an unexpectedly strong binding affinity for PDREs, suggesting a role in transcriptional activation separate from histone modulation. They further show that Rtt106p works through the PDR gene PDR3, a transcriptional activator, to regulate basal expression of PDR-related genes. They found that basal expression of PDR5, the main multidrug transporter of the PDR pathway, requires Rtt106p binding the PDR5 promoter in concert with Pdr3p.
In response to drugs, however, a different set of regulators come into play. The authors show that neither RTT106 nor PDR3 is responsible for drug induction of resistance genes, but rather that PDR1 is critical for drug-induced upregulation of PDR5. By means of the minichromosome isolation technique, they further show how a different histone-modulating mechanism—the SWI/SNF ATP-dependent chromatin-remodeling complex—both binds to and activates the PDR5 promoter in response to an azole-type antifungal drug.
As the goal of this work was to better understand PDR in pathogenic yeasts, the team next looked at the orthologs of the histone modulation genes in C. glabrata. The summary of their findings is that neither CgRtt106 nor CgSWI/SNF acts in maintenance of basal expression of PDR network genes, but each is clearly required for drug-induced expression. From this work, the authors conclude that these chromatin modulators studied in budding yeast constitute potential therapeutic targets in the pathogenic yeast. The use of a tractable model yeast has once more proven its value in combat of fungal multidrug resistance.
Categories: Research Spotlight