Comparative genomic and transcriptomic analyses unveil novel features of azole resistance and adaptation to the human host in Candida glabrata

Abstract

The frequent emergence of azole resistance among Candida glabrata strains contributes to increase the incidence of infections caused by this species. Whole-genome sequencing of a fluconazole and voriconazole-resistant clinical isolate (FFUL887) and subsequent comparison with the genome of the susceptible strain CBS138 revealed prominent differences in several genes documented to promote azole resistance in C. glabrata. Among these was the transcriptional regulator CgPdr1. The CgPdr1 FFUL887 allele included a K274Q modification not documented in other azole-resistant strains. Transcriptomic profiling evidenced the upregulation of 92 documented targets of CgPdr1 in the FFUL887 strain, supporting the idea that the K274Q substitution originates a CgPdr1 gain-of-function mutant. The expression of CgPDR1K274Q in the FFUL887 background sensitised the cells against high concentrations of organic acids at a low pH (4.5), but had no detectable effect in tolerance towards other environmental stressors. Comparison of the genome of FFUL887 and CBS138 also revealed prominent differences in the sequence of adhesin-encoding genes, while comparison of the transcriptome of the two strains showed a significant remodelling of the expression of genes involved in metabolism of carbohydrates, nitrogen and sulphur in the FFUL887 strain; these responses likely reflecting adaptive responses evolved by the clinical strain during colonisation of the host.

Fungal resistance to echinocandins and the MDR phenomenon in Candida glabrata

“…The presence of a PDR1 mutation appears to increase the ability of C. glabrata to adapt to other stressors, including echinocandin exposure. Specific PDR1 mutations in C. glabrata not only confer azole resistance, but can also enhance adhesion to epithelial cells through increased expression of the epithelial adhesin gene EPA1 [61][62][63][64]. The genome of C. glabrata carries a large number of EPA (epithelial adhesin) genes that encode for adhesin proteins [65][66][67].…”

An Overview on Conventional and Non-Conventional Therapeutic Approaches for the Treatment of Candidiasis and Underlying Resistance Mechanisms in Clinical Strains

“…The overexpression of drug-efflux pump-encoding genes results, in many cases, from the occurrence of activating mutations in the coding sequence of the corresponding regulators [41,45,78,82,[85][86][87][88][89]. This type of mechanism has been documented for CgPdr1 in C. glabrata; for CaTac1, CaMrr1 and CaUpc2 in C. albicans and for CpMrr1 and CpTac1 in C. parapsilosis [41,45,78,82,85,88].…”

“…It thus seems that specialization of the cells to improve azole stress at the expense of CaTac1 hyper-activation results in reduced capacity to handle unrelated stresses. In the same line, the expression of CgPdr1 gain-of-function alleles were also hypothesized to be linked with a reduced tolerance of C. glabrata to organic acids [51,68,89,91].…”

“…Summary of the mechanisms of resistance registered in azole-resistant Candida isolates, as described in[40][41][42][43]72,[76][77][78][79]82,[85][86][87][88][89]92,93,96,[111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128].…”

Strong population structure in Venezuelan populations ofCoccidioides posadasii

“…Systematic surveys of genetic diversity of fungal pathogens have revealed extensive variability in the strength of virulence among genotypes of isolates from the same species (e.g., (7)). Other traits like antifungal resistance, and ability to survive different environmental conditions also show extensive variation (8–10). Understanding the magnitude and sources of variation among these traits is a crucial aspect of understanding why some pathogens are more effective at spreading and causing disease than others.…”