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Review
. 2023 Jun 15;11(3):e0049823.
doi: 10.1128/spectrum.00498-23. Epub 2023 Apr 25.

High-Throughput Profiling of Candida auris Isolates Reveals Clade-Specific Metabolic Differences

Philipp Brandt #  1 , Mohammad H Mirhakkak #  2 , Lysett Wagner  1 , Dominik Driesch  3 , Anna Möslinger  1   4 , Pauline Fänder  1 , Sascha Schäuble  2 , Gianni Panagiotou  2 , Slavena Vylkova  1
Affiliations
Review

High-Throughput Profiling of Candida auris Isolates Reveals Clade-Specific Metabolic Differences

Philipp Brandt et al. Microbiol Spectr. .

Abstract

Candida auris, a multidrug-resistant human fungal pathogen that causes outbreaks of invasive infections, emerged as four distinct geographical clades. Previous studies identified genomic and proteomic differences in nutrient utilization on comparison to Candida albicans, suggesting that certain metabolic features may contribute to C. auris emergence. Since no high-throughput clade-specific metabolic characterization has been described yet, we performed a phenotypic screening of C. auris strains from all 4 clades on 664 nutrients, 120 chemicals, and 24 stressors. We identified common and clade- or strain-specific responses, including the preferred utilization of various dipeptides as nitrogen source and the inability of the clade II isolate AR 0381 to withstand chemical stress. Further analysis of the metabolic properties of C. auris isolates showed robust growth on intermediates of the tricarboxylic acid cycle, such as citrate and succinic and malic acids. However, there was reduced or no growth on pyruvate, lactic acid, or acetate, likely due to the lack of the monocarboxylic acid transporter Jen1, which is conserved in most pathogenic Candida species. Comparison of C. auris and C. albicans transcriptomes of cells grown on alternative carbon sources and dipeptides as a nitrogen source revealed common as well as species-unique responses. C. auris induced a significant number of genes with no ortholog in C. albicans, e.g., genes similar to the nicotinic acid transporter TNA1 (alternative carbon sources) and to the oligopeptide transporter (OPT) family (dipeptides). Thus, C. auris possesses unique metabolic features which could have contributed to its emergence as a pathogen. IMPORTANCE Four main clades of the emerging, multidrug-resistant human pathogen Candida auris have been identified, and they differ in their susceptibilities to antifungals and disinfectants. Moreover, clade- and strain-specific metabolic differences have been identified, but a comprehensive overview of nutritional characteristics and resistance to various stressors is missing. Here, we performed high-throughput phenotypic characterization of C. auris on various nutrients, stressors, and chemicals and obtained transcriptomes of cells grown on selected nutrients. The generated data sets identified multiple clade- and strain-specific phenotypes and induction of C. auris-specific metabolic genes, showing unique metabolic properties. The presented work provides a large amount of information for further investigations that could explain the role of metabolism in emergence and pathogenicity of this multidrug-resistant fungus.

Keywords: Candida auris; Jen2; carboxylic acids; dicarboxylic acids; dipeptide transport; dipeptides; metabolism; phenotypic profiling.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIG 1
FIG 1
Phenotypic screen of C. auris isolates on various carbon sources. Biolog Phenotypic MicroArray plates PM1 and PM2 (carbon sources) for fungi were used to measure the metabolic activity of C. auris isolates kinetically every 15 min for 48 h at 37°C. The bars represent the calculated means and standard deviations of the AUC of selected carbon sources of three biological replicates per strain.
FIG 2
FIG 2
Phenotypic screen of C. auris isolates on various phosphorus and sulfur sources. Biolog Phenotypic MicroArray plate PM4 (phosphorus and sulfur sources) for fungi was used to measure the metabolic activity of C. auris isolates kinetically every 15 min for 48 h at 37°C. The bars represent the calculated means and standard deviations of the AUC of three biological replicates per strain grown on phosphoenolpyruvate (A), l-methionine (B), or Gly-Met (C).
FIG 3
FIG 3
Growth curves of C. auris isolates on various nitrogen sources. SD overnight cultures were adjusted to an OD600 of 0.1 in YCB medium containing either 0.5% ammonium sulfate (A) or a 10 mM concentration of GlcNAc (B), His-Ala (C), or His-Ser (D) and incubated at 37°C with shaking. The OD600 was measured after 24 h and 48 h. The values shown are the calculated means and standard deviations of three biological replicates. Altogether, our growth experiments were consistent with the results of the phenotypic microarray screen.
FIG 4
FIG 4
C. auris has an impaired ability to utilize monocarboxylic acids. SD overnight cultures of the strains were adjusted to an OD600 of 1.0. Serial 10-fold dilutions were spotted onto agar plates containing 1% glucose or 1% of the di- or tricarboxylic acid (A), and 1% glucose or 1% of the indicated monocarboxylic acid (B). Plates were incubated for 3 days at 37°C.
FIG 5
FIG 5
The phylogenetic tree of S. cerevisiae Jen1 homologs identified one homolog in C. auris. The phylogenetic tree of S. cerevisiae Jen1 homologs was generated by using the Galaxy platform to set up a BLAST database with public genome data followed by the identification of homologous sequences in C. auris and related species by applying the tblastn tool. The gene ID is given in the label (e.g., CAWG_03392).
FIG 6
FIG 6
Principal-component analysis of C. albicans SC5314 and C. auris AR 0387. Transcriptional profiling was performed with C. albicans and C. auris cells grown on different carbon sources (glucose, malic acid, α-ketoglutarate, proline) or on a mixture of dipeptides (3.4 mM Ala-Gln, 3.3 mM Ala-Ser, 3.3 mM Arg-Asp) as a nitrogen source. Each color represents a different medium condition of three biological replicates of C. albicans strain SC5314 and C. auris strain AR 0387.
FIG 7
FIG 7
Transcriptional response of C. albicans strain SC5314 to malic acid, α-ketoglutaric acid, and proline as a C source. (A) Venn diagrams representing all significantly differentially regulated genes with a log2 fold change of >1 (blue) and <(−1) (Zamith-Miranda [45]) and a P value of <0.05. (B) Gene ontology analyses of the upregulated (blue, n = 142) and downregulated (red, n = 236) core sets of genes were performed by using the GO term finder and with “process” as a query, followed by using the Revigo tool (http://revigo.irb.hr/). Only the 10 most significant enriched GO terms, defined by a −log10 value of 0.05, are shown and are indicated by a dashed line at 1.3 on the x axis.
FIG 8
FIG 8
Transcriptional response of C. auris strain AR 0387 to malic acid, α-ketoglutaric acid, and proline as C sources. (A) Venn diagrams representing all significantly differentially regulated genes with a log2 fold change of >1 (blue) and <(−1) (Zamith-Miranda [45]) and a P value of <0.05 (blue). (B) Gene ontology analyses of the upregulated and downregulated core sets of genes that have an ortholog in C. albicans were performed by using the GO term finder and “process” as a query, followed by using the Revigo tool (http://revigo.irb.hr/). Only the 10 most significant enriched GO terms, defined by a −log10 of 0.05, are shown (indicated by a dashed line at 1.3 on the x axis).
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