Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Sep;130(9):568-577.
doi: 10.1111/apm.13260. Epub 2022 Jul 20.

Screening the Tocriscreen™ bioactive compound library in search for inhibitors of Candida biofilm formation

Hafsa Abduljalil #  1 , Ahmed Bakri #  1 , Khawlah Albashaireh #  1 , Om Alkhir Alshanta  1 , Jason L Brown  1 , Leighann Sherry  1 , Ryan Kean  2 , Christopher Nile  3 , William McLean  1 , Gordon Ramage  1
Affiliations

Screening the Tocriscreen™ bioactive compound library in search for inhibitors of Candida biofilm formation

Hafsa Abduljalil et al. APMIS. 2022 Sep.

Abstract

Biofilms formed by Candida species present a significant clinical problem due to the ineffectiveness of many conventional antifungal agents, in particular the azole class. We urgently require new and clinically approved antifungal agents quickly for treatment of critically ill patients. To improve efficiency in antifungal drug development, we utilized a library of 1280 biologically active molecules within the Tocriscreen 2.0 Micro library. Candida auris NCPF 8973 and Candida albicans SC5314 were initially screened for biofilm inhibitory activity using metabolic and biomass quantitative assessment methods, followed up by _targeted evaluation of five selected hits. The initial screening (80% metabolic inhibition rate) revealed that there was 90 and 87 hits (approx. 7%) for C. albicans and C. auris, respectively. Additionally, all five compounds selected from the initial hits exhibited a biofilm inhibition effect against several key Candida species tested, including C. glabrata and C. krusei. Toyocamycin displayed the most potent activity at concentrations as low as 0.5 μg/mL, though was limited to inhibition. Darapladib demonstrated an efficacy for biofilm inhibition and treatment at a concentration range from 8 to 32 μg/mL and from 16 to 256 μg/mL, respectively. Combinational testing with conventional antifungals against C. albicans strains demonstrated a range of synergies for planktonic cells, and notably an anti-biofilm synergy for darapladib and caspofungin. Together, these data provide new insights into antifungal management possibilities for Candida biofilms.

Keywords: Candida albicans; Candida auris; Biofilm; drug repurposing.

PubMed Disclaimer

Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
A total of 1280 compounds from Tocris 2.0 micro library were screened against (A) Candida albicans SC5314 and (B) Candida auris 8973. Orange and green colour dotted lines indicate percentage of inhibition (MBIC) at 50% and 80%, respectively. Red dots represent the percentage of inhibition of the five hits selected for further assessment in this study (C) Venn diagram showing the overlapping compounds between C. albicans SC5314 and C. auris 8973 during the initial screening of 1280 compounds at 80% inhibition. [Colour figure can be viewed at wileyonlinelibrary.com]
Fig. 2
Fig. 2
Heatmaps showing the synergistic inhibition of planktonic Candida albicans (SC5314) by (A) toyocamycin combined with fluconazole, (B) Darapladib with fluconazole, and (C) Darapladib with Caspofungin, utilizing the checkerboard microdilution assay (MBIC). Different starting concentrations used for Toyocamycin (8 μg/mL), Darapladib (64 μg/mL), Fluconazole (32 μg/mL) and Caspofungin (2 μg/mL). Directional arrows represent a serial doubling reduction from the stated concentration. Growth was measured at 490 nm OD, and values represent median from three biological replicates with three technical repeats. [Colour figure can be viewed at wileyonlinelibrary.com]
Fig. 3
Fig. 3
Heatmap showing the synergistic killing of Candida albicans (SC5314) biofilm by the combination of Darapladib with Caspofungin utilizing the checkerboard microdilution assay (MBKC). Starting concentration of Darapladib is 128 μg/mL and for caspofungin 2 μg/mL. Directional arrows represent a serial doubling reduction from the stated concentration. Growth was measured at 490 nm OD, and values represent median from three biological replicates with three technical repeats. [Colour figure can be viewed at wileyonlinelibrary.com]
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Tumbarello M, Posteraro B, Trecarichi EM, Fiori B, Rossi M, Porta R, et al. Biofilm production by Candida species and inadequate antifungal therapy as predictors of mortality for patients with candidemia. J Clin Microbiol. 2007;45(6):1843–50. - PMC - PubMed
    1. Atiencia‐Carrera MB, Cabezas‐Mera FS, Tejera E, Machado A. Prevalence of biofilms in Candida spp. bloodstream infections: a meta‐analysis. PLoS One 2022;17(2):e0263522. - PMC - PubMed
    1. Ramage G, Tomsett K, Wickes BL, Lopez‐Ribot JL, Redding SW. Denture stomatitis: a role for Candida biofilms. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;98(1):53–9. - PubMed
    1. Rajendran R, Sherry L, Nile CJ, Sherriff A, Johnson EM, Hanson MF, et al. Biofilm formation is a risk factor for mortality in patients with Candida albicans bloodstream infection‐Scotland, 2012‐2013. Clin Microbiol Infect. 2016;22(1):87–93. - PMC - PubMed
    1. Tsui C, Kong EF, Jabra‐Rizk MA. Pathogenesis of Candida albicans biofilm. Pathog Dis. 2016;74(4):ftw018. - PMC - PubMed

Substances

  NODES
chat 1
twitter 2