Inhibitors of the glyoxylate cycle enzyme ICL1 in Candida albicans for potential use as antifungal agents.

Hong-Leong Cheah,Vuanghao Lim,Doblin Sandai,Alix Therese Coste

doi:10.1371/journal.pone.0095951

Hong-Leong Cheah, Vuanghao Lim + Show 2 more

Open Access

https://doi.org/10.1371/journal.pone.0095951

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Journal: PloS one	Publication Date: Apr 29, 2014
Citations: 82	License type: CC BY 4.0

Affiliation: Universiti Sains Malaysia

Abstract

Candida albicans is an opportunistic pathogen that causes candidiasis in humans. In recent years, metabolic pathways in C. albicans have been explored as potential antifungal targets to treat candidiasis. The glyoxylate cycle, which enables C. albicans to survive in nutrient-limited host niches and its. Key enzymes (e.g., isocitrate lyase (ICL1), are particularly attractive antifungal targets for C. albicans. In this study, we used a new screening approach that better reflects the physiological environment that C. albicans cells experience during infection to identify potential inhibitors of ICL. Three compounds (caffeic acid (CAFF), rosmarinic acid (ROS), and apigenin (API)) were found to have antifungal activity against C. albicans when tested under glucose-depleted conditions. We further confirmed the inhibitory potential of these compounds against ICL using the ICL enzyme assay. Lastly, we assessed the bioavailability and toxicity of these compounds using Lipinski's rule-of-five and ADMET analysis.

Highlights

Candida albicans and other medically relevant Candida species are mainly common commensal yeasts that inhabit mucosal surfaces and the gastrointestinal and genitourinary tracts [1]
Antifungal Drug and Reference Compounds The antifungal drug used as the control in this study, fluconazole (FLC), and the plant reference compounds, itaconic acid (ITC), quercetin (QCT), cinnamic acid (CINN), rutin (RT), caffeic acid (CAFF), gallic acid (GALL), apigenin (API), and rosmarinic acid (ROS) (Figure 2), were purchased from SigmaAldrich Co
Secondary screening, which included the assessment of growth in YNBG, further narrowed the list to three potential isocitrate lyase (ICL) inhibitors (CAFF, API, and ROS) that showed a lactate-specific pattern of growth reduction (Figure 3)

Summary

Introduction

Candida albicans and other medically relevant Candida species are mainly common commensal yeasts that inhabit mucosal surfaces and the gastrointestinal and genitourinary tracts [1]. They are usually benign but can become infectious if an environmental niche becomes available or the host immune system becomes impaired [2]. Choices of antifungal drugs to treat candidiasis are limited Those that are in routine clinical use include the polyenes, azoles, and echinocandins [2]. In recent years metabolic pathways have been explored as potential antifungal targets, as they contribute to the metabolic flexibility that allows cells to survive in nutrient-limited host niches during infection [4]. Metabolic flexibility is crucial for C. albicans and other pathogenic fungi for survival in nutrient-limited host niches as it contributes to effective assimilation of different carbon sources [7]

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Conclusion