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Cited by 395Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Infections and Studies

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The Emerging Pathogen Candida auris: Growth Phenotype, Virulence Factors, Activity of Antifungals, and Effect of SCY-078, a Novel Glucan Synthesis Inhibitor, on Growth Morphology and Biofilm Formation

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Larkin, Emily, Hager, Christopher, Chandra, Jyotsna, Mukherjee, Pranab K., Retuerto, Mauricio, Salem, Iman, Long, Lisa, Isham, Nancy, Kovanda, Laura, Borroto-Esoda, Katyna, Wring, Steve, Angulo, David, Ghannoum, Mahmoud·2017·Antimicrobial Agents and Chemotherapy
DOI 10.1128/aac.02396-16PMC PMC5404565
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Abstract

Candida auris , a new multidrug-resistant Candida spp. which is associated with invasive infection and high rates of mortality, has recently emerged. Here, we determined the virulence factors (germination, adherence, biofilm formation, phospholipase and proteinase production) of 16 C. auris isolates and their susceptibilities to 11 drugs belonging to different antifungal classes, including a novel orally bioavailable 1,3-β- d -glucan synthesis inhibitor (SCY-078). We also examined the effect of SCY-078 on the growth, ultrastructure, and biofilm-forming abilities of C. auris . Our data showed that while the tested strains did not germinate, they did produce phospholipase and proteinase in a strain-dependent manner and had a significantly reduced ability to adhere and form biofilms compared to that of Candida albicans ( P = 0.01). C. auris isolates demonstrated reduced susceptibility to fluconazole and amphotericin B, while, in general, they were susceptible to the remaining drugs tested. SCY-078 had an MIC 90 of 1 mg/liter against C. auris and caused complete inhibition of the growth of C. auris and C. albicans . Scanning electron microscopy analysis showed that SCY-078 interrupted C. auris cell division, with the organism forming abnormal fused fungal cells. Additionally, SCY-078 possessed potent antibiofilm activity, wherein treated biofilms demonstrated significantly reduced metabolic activity and a significantly reduced thickness compared to the untreated control ( P < 0.05 for both comparisons). Our study shows that C. auris expresses several virulence determinants (albeit to a lesser extent than C. albicans ) and is resistant to fluconazole and amphotericin B. SCY-078, the new orally bioavailable antifungal, had potent antifungal/antibiofilm activity against C. auris , indicating that further evaluation of this antifungal is warranted.

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FIG 1 Comparison of adherence of C. auris strains. The ability of Candida species to adhere to a silicon elastomer catheter as a representative substrate was assessed. Cells were allowed to adhere to silicone elastomer discs, washed, and overlaid with Sabouraud dextrose agar, and the number of CFU adhering to the substrate was counted after incubation at 37°C for 18 to 24 h. The number of adherent C. auris cells was significantly less than that for C. albicans (positive control) (P ≤ 0.01). *, P value compared to the value for C. albicans.
FIG 1 Comparison of adherence of C. auris strains. The ability of Candida species to adhere to a silicon elastomer catheter as a representative substrate was assessed. Cells were allowed to adhere to silicone elastomer discs, washed, and overlaid with Sabouraud dextrose agar, and the number of CFU adhering to the substrate was counted after incubation at 37°C for 18 to 24 h. The number of adherent C. auris cells was significantly less than that for C. albicans (positive control) (P ≤ 0.01). *, P value compared to the value for C. albicans.CC BY · PubMed Central
FIG 2 Formation of biofilms by C. albicans and C. auris strains. Confocal scanning laser micrographs show top-down three-dimensional views (A to C) and side views (D to F) of biofilms formed by C. albicans (A, D), C. auris MRL 31102 (B, E), and C. auris MRL 31103 (C, F). Magnifications, ×100. (G) Thickness of biofilms formed by the tested isolates. *, P value compared to the thickness of C. albicans biofilms. A P value of <0.05 was considered significant. All experiments were done in triplicate, and data represent means ± SDs. C. albicans SC5314 showed a highly heterogeneous architecture of biofilms with yeast cells and hyphae embedded within the extracellular matrix, while C. auris biofilms had minimal extracellular matrix and were significantly thinner than C. albicans biofilms.
FIG 2 Formation of biofilms by C. albicans and C. auris strains. Confocal scanning laser micrographs show top-down three-dimensional views (A to C) and side views (D to F) of biofilms formed by C. albicans (A, D), C. auris MRL 31102 (B, E), and C. auris MRL 31103 (C, F). Magnifications, ×100. (G) Thickness of biofilms formed by the tested isolates. *, P value compared to the thickness of C. albicans biofilms. A P value of <0.05 was considered significant. All experiments were done in triplicate, and data represent means ± SDs. C. albicans SC5314 showed a highly heterogeneous architecture of biofilms with yeast cells and hyphae embedded within the extracellular matrix, while C. auris biofilms had minimal extracellular matrix and were significantly thinner than C. albicans biofilms.CC BY · PubMed Central
FIG 3 Quantification of biofilms formed by C. albicans and C. auris strains. The metabolic activity (A) and dry weight (B) of the biofilms formed by C. albicans, C. auris MRL 31102 (control), and 14 CBS C. auris strains are shown. *, P value compared to the results for C. albicans. A P value of <0.05 was considered significant. All experiments were done in triplicate, and the data in both plots represent means ± SDs. C. auris biofilms had significantly reduced metabolic activity and biomass compared to those of C. albicans biofilms.
FIG 3 Quantification of biofilms formed by C. albicans and C. auris strains. The metabolic activity (A) and dry weight (B) of the biofilms formed by C. albicans, C. auris MRL 31102 (control), and 14 CBS C. auris strains are shown. *, P value compared to the results for C. albicans. A P value of <0.05 was considered significant. All experiments were done in triplicate, and the data in both plots represent means ± SDs. C. auris biofilms had significantly reduced metabolic activity and biomass compared to those of C. albicans biofilms.CC BY · PubMed Central
FIG 4 Effect of different concentrations of the antifungal SCY-078 on the growth of C. albicans and C. auris isolates. C. albicans SC5314 (A), C. auris MRL 31102 (B), and C. auris MRL 31103 (C) cells were grown in the presence of the indicated concentrations of SCY-078. At different time points, aliquots were withdrawn and their ODs were determined spectrophotometrically. All experiments were done in triplicate, and the data in all three panels represent means ± SDs. SCY-078 inhibited the growth of the C. albicans and C. auris strains.
FIG 4 Effect of different concentrations of the antifungal SCY-078 on the growth of C. albicans and C. auris isolates. C. albicans SC5314 (A), C. auris MRL 31102 (B), and C. auris MRL 31103 (C) cells were grown in the presence of the indicated concentrations of SCY-078. At different time points, aliquots were withdrawn and their ODs were determined spectrophotometrically. All experiments were done in triplicate, and the data in all three panels represent means ± SDs. SCY-078 inhibited the growth of the C. albicans and C. auris strains.CC BY · PubMed Central
FIG 5 Scanning electron micrograph of C. auris treated with no drug (control) (A) and with SCY-078 at 1× MIC (0.5 mg/liter) (B). Cells were exposed to no drug (control) or SCY-078 at 1× MIC overnight at 35°C and then fixed in 2% glutaraldehyde and processed for scanning electron microscopy. Untreated control C. auris cells had a well-defined, oval-shaped yeast morphology as well as several budding yeasts (A). In contrast, cells exposed to SCY-078 (at a concentration of 1× MIC) exhibited a severely distorted yeast cell topography with cells fused together, indicating that the cells were unable to divide (B). Magnifications, ×6,000.
FIG 5 Scanning electron micrograph of C. auris treated with no drug (control) (A) and with SCY-078 at 1× MIC (0.5 mg/liter) (B). Cells were exposed to no drug (control) or SCY-078 at 1× MIC overnight at 35°C and then fixed in 2% glutaraldehyde and processed for scanning electron microscopy. Untreated control C. auris cells had a well-defined, oval-shaped yeast morphology as well as several budding yeasts (A). In contrast, cells exposed to SCY-078 (at a concentration of 1× MIC) exhibited a severely distorted yeast cell topography with cells fused together, indicating that the cells were unable to divide (B). Magnifications, ×6,000.CC BY · PubMed Central
FIG 6 Confocal scanning laser microscopy analyses of the effect of SCY-078 on biofilms formed by C. auris. Biofilms formed by C. auris MRL 31102 were exposed to no drug (control) (A, E) or SCY-078 at different concentrations: 0.5 mg/liter (B, F), 2 mg/liter (C, G), or 4 mg/liter (D, H). Top-down views (A to D) and side views (E to H) of untreated and treated biofilms are shown. Magnifications, ×25. (I and J) The thickness (I) and metabolic activity (J) of untreated (control) and SCY-078-treated biofilms. *, P value compared to the results for the untreated control (no drug). A P value of <0.05 was considered significant. All experiments were done in triplicate, and the bars represent means ± SDs. SCY-078 exhibited potent activity against biofilms formed by C. auris strains.
FIG 6 Confocal scanning laser microscopy analyses of the effect of SCY-078 on biofilms formed by C. auris. Biofilms formed by C. auris MRL 31102 were exposed to no drug (control) (A, E) or SCY-078 at different concentrations: 0.5 mg/liter (B, F), 2 mg/liter (C, G), or 4 mg/liter (D, H). Top-down views (A to D) and side views (E to H) of untreated and treated biofilms are shown. Magnifications, ×25. (I and J) The thickness (I) and metabolic activity (J) of untreated (control) and SCY-078-treated biofilms. *, P value compared to the results for the untreated control (no drug). A P value of <0.05 was considered significant. All experiments were done in triplicate, and the bars represent means ± SDs. SCY-078 exhibited potent activity against biofilms formed by C. auris strains.CC BY · PubMed Central

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Research works printed but not linked: 3

  1. Odds FC . 1988. Candida and candidosis: a review and bibliography, 2nd ed, vol 1. Bailliere Tindall, London, England.
  2. Kwon-Chung KJ BennettJE. 1992. Medical mycology. Lea & Febiger, Philadelphia, PA.
  3. Clinical and Laboratory Standards Institute. 2008. Reference method for broth dilution antifungal susceptibility testing of yeasts, 3rd ed. Approved standard M27-A3. Clinical and Laboratory Standards Institute, Wayne, PA.

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Metadata

Authors
Larkin, E., Hager, C., Chandra, J., Mukherjee, P. K., Retuerto, M., Salem, I., Long, L., Isham, N., Kovanda, L., Borroto-Esoda, K., Wring, S., Angulo, D., & Ghannoum, M.
Affiliations
  • University Hospitals of Cleveland (US)
  • Astellas Pharma (United States) (US)
  • Scynexis Inc., Jersey City, New Jersey, USA
  • Scynexis (United States) (US)
Corresponding author
Ghannoum, Mahmoud
ORCID
Venue
Antimicrobial Agents and Chemotherapy
Publisher
American Society for Microbiology
Published
2017-05
Volume
61
Issue
5
ISSN
  • 0066-4804 (ISSN-L)
  • 1098-6596
DOI
10.1128/aac.02396-16
PMC
PMC5404565
OpenAlex
W2589939125
Cited by
395
References
53
Citations by year
2026: 24 · 2025: 25 · 2024: 31 · 2023: 36 · 2022: 30 · 2021: 49 · 2020: 67 · 2019: 51 · 2018: 42 · 2017: 39
FWCI
42.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Antimicrobial Agents and Chemotherapy (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Case Western Reserve University
  • National Institutes of Health
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR039750)
  • National Institute of Dental and Craniofacial Research (R01DE024228)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Health Sciences › Medicine › Infectious Diseases › Fungal Infections and Studies
Keywords
Candida auris, antifungal susceptibility, fluconazole resistance, amphotericin B resistance, biofilm formation, antibiofilm activity, fungal virulence factors, phospholipase, proteolytic enzymes, fungal adhesion, cell division inhibition, Candida albicans comparison, multidrug-resistant fungi
MeSH terms
Amphotericin B, Antifungal Agents, Candida, Candida albicans, Candidiasis, Cell Adhesion, Cell Division, Glucans, Glycosides, Humans, Microbial Sensitivity Tests, Peptide Hydrolases, Phospholipases, Triterpenes, Fluconazole, Biofilms, Drug Resistance, Multiple, Fungal, Virulence Factors

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