Isocitrate lyase of Candida albicans is inhibited by Octyl Gallate
Venkata Saibabu1, Kamal Ahmad1, Saif Hameed2, Luqman Ahmad Khan1*,
1Department of Bio Sciences, Jamia Millia Islamia, New Delhi-110025, India.

2Amity Institute of Biotechnology, Amity University Haryana, Gurgaon- 122413, India.

Aim or purpose:
The increment in the immunocompromised conditions with concomitant resistance in Candida albicans against current therapeutic drugs is compelling us to categorize new drugs with novel targets. The metabolic pathways such as glyoxylate cycle (GC) enable C. albicans, to survive under glucose deficient conditions prevalent in the hostile niche. Thus, its key enzymes (Isocitrate lyase; ICL1) represent attractive targets against C. albicans. The present study led to the identification of Octyl gallte (OG) as a potent GC inhibitor.
Materials and methods:
Different Candida species were tested according to the CLSI protocol to determine the minimum inhibitory concentrations. Confocal microscopy was used to assess the propidium iodide uptake. Docking studies were performed using AutoDock 4.2 package. The interaction between ICL and OG were analyzed using the Lamarckian genetic algorithm. The binding energy was calculated using van der Waals, electrostatic interactions and hydrogen bonding. In vitro biochemical assays for ICL1 enzyme activity was performed with isocitric acid as substrate. Biofilm inhibition in the presence of OG was evaluated by quantification of the biofilm metabolic activity with MTT. Inhibition of hyphal formation in the presence of OG was evaluated by growing the cells in hyphal inducing conditions. Toxicity of the OG was evaluated using human blood cells. OG in vivo efficacy was evaluated for C. albicans, using Caenorhabditis elegans model.
OG shows potent antifungal activity against C. albicans and non-albicans candida species ranging from 12.5-25µg/ml. In silico an in vitro studies showed that OG acts as potent inhibitor of ICL1 activity. Furthermore, OG was able to enhance the survival of Caenorhabditis elegans infected with C. albicans.
These findings indicate that OG has excellent in vitro activity against C. albicans. We present preliminary evidence that OG activity against C. albicans through inhibiting ICL1 activity. We demonstrated the antifungal potential for OG against C. albicans infections by enhanced survival of Caenorhabditis elegans and less hemolytic activity (27%) on human blood cells. Further studies are warranted for OG to be considered as viable drug candidate.