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

by Selleckchem | Jun 12 2023

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.

Comments:

The study focused on identifying potential antifungal agents for the treatment of Candida biofilms, which are known to be problematic due to their resistance to conventional antifungal drugs, particularly azoles. The researchers used a library of 1280 biologically active molecules called Tocriscreen 2.0 Micro to screen for biofilm inhibitory activity against Candida auris NCPF 8973 and Candida albicans SC5314. They initially employed metabolic and biomass quantitative assessment methods to evaluate the inhibitory effects of the compounds.

The screening results showed that approximately 7% of the compounds (90 hits for C. albicans and 87 hits for C. auris) exhibited a high level of biofilm inhibitory activity with an 80% metabolic inhibition rate. The researchers then selected five compounds from these initial hits for further evaluation. These compounds demonstrated biofilm inhibition effects against various Candida species, including C. glabrata and C. krusei. Among the five compounds, toyocamycin displayed the most potent activity, inhibiting biofilm formation at concentrations as low as 0.5 μg/mL.

Another compound called darapladib showed efficacy both in inhibiting biofilm formation (at concentrations ranging from 8 to 32 μg/mL) and treating established biofilms (at concentrations ranging from 16 to 256 μg/mL). Furthermore, when darapladib was tested in combination with conventional antifungal drugs against C. albicans strains, it exhibited synergistic effects for planktonic cells and notably demonstrated an anti-biofilm synergy when combined with caspofungin.

These findings provide valuable insights into the management of Candida biofilms and suggest new possibilities for antifungal treatment. The identified compounds, especially toyocamycin and darapladib, hold promise as potential candidates for the development of clinically approved antifungal agents that could be used in the treatment of critically ill patients. However, further research and clinical trials are necessary to validate their efficacy and safety before they can be widely implemented in clinical settings.