Jjj1 Is a Negative Regulator of Pdr1-Mediated Fluconazole Resistance in Candida glabrata

Abstract

Candida glabrata is the second most common species of Candida recovered from patients with invasive candidiasis. The increasing number of infections due to C. glabrata, combined with its high rates of resistance to the commonly used, well-tolerated azole class of antifungal agents, has limited the use of this antifungal class. This has led to the preferential use of echinocandins as empirical treatment for serious Candida infections. The primary mechanism of resistance found in clinical isolates is the presence of an activating mutation in the gene encoding the transcription factor Pdr1 that results in upregulation of one or more of the efflux pumps Cdr1, Pdh1, and Snq2. By developing a better understanding of this mechanism of resistance to the azoles, it will be possible to develop strategies for reclaiming the utility of the azole antifungals against this important fungal pathogen.

Functional information from clinically-derived drug resistant forms of the Candida glabrata Pdr1 transcription factor

“…The C-terminal activation domain of Pdr1 (residues 968-1107) may be released from intramolecular repression by changes such as D1082G, LWG1097AAA, multiple mutations in the CRD or deletion of the entire CRD as in the internal deletion Δ255-968 Pdr1. It is also possible that interactions with the trans-acting negative regulators Bre5 and Jjj1 might also be involved in the effects seen for the impact of C-terminal mutagenesis [14,15]. We speculate that the D1082 and LWG1097 regions also have positive interactions with co-activators other than Med15A as the combination of mutational alterations in these two regions, coupled with deletion of MED15A, caused the most profound defect in Pdr1-mediated fluconazole resistance and Cdr1 expression (Fig 8).…”

“…Experiments aimed at identifying interacting proteins with the Pdr1 TAD demonstrated the Mediator subunit Med15A binds to the C-terminal 34 residues and provided evidence that this binding is required to fully drive induced gene expression [13]. Genetic and biochemical experiments have identified two trans-acting negative regulators of Pdr1 activity-Jjj1 and Bre5, although their target region within Pdr1 remains unknown [14,15]. While a broad spectrum of GOF forms of Pdr1 have been identified, how these lesions trigger the high-level transactivation of Pdr1 target genes is not understood.…”

Transcriptome analysis of fungicide-responsive gene expression profiles in two Penicillium italicum strains with different response to the sterol demethylation inhibitor (DMI) fungicide prochloraz

“…RNA sequencing (RNA-seq) technology has become a powerful tool to profile transcriptomic response to reveal azole-resistance mechanism for some pathogenic fungi including prochloraz-resistant P. digitatum [11], voriconazole-resistant A. fumigatus [81], tetraconazoleresistant Cercospora beticola [82], tebuconazole-resistant Fusarium culmorum [83], and fluconazole-resistant Candida glabrata [84]. Our earlier report has elucidated the mechanism of P. digitatum resistance to DMIfungicide prochloraz through RNA-seq analysis [11].…”

Probe-based qPCR Assay for Rapid Detection of Predominant Candida glabrata Sequence Type in Korea

“…Notably, C. glabrata has a wide minimum inhibitory concentration (MIC) range (≤ 32 μg/mL) for fluconazole susceptible-dose dependence (SDD) with no MIC cut-off for the susceptible range, according to the Clinical and Laboratory Standards Institute (CLSI). However, despite fluconazole's wide MIC range, C. glabrata has demonstrated reduced susceptibility and high-level resistance to fluconazole therapy (Whaley et al, 2018). The mortality rate of candidemia caused by C. glabrata is also increasing, becoming higher than other NAC species due to resistance to azole antifungal agents (Gohar et al, 2017).…”