Synergistic potential of Citrus aurantium L. essential oil with antibiotics against Candida albicans

Ethnopharmacological relevance: Citrus aurantium L. is used in traditional medicine for treating stomach ache, vomiting, blood pressure, dysentery, diarrhea, cardiovascular analeptic, sedative, boils and urinary tract infections. Its essential oil from fruit peels has antioxidant, antimicrobial, antifungal, antiparasitic, and anti-inflammatory activities.

Aim of the study: The aim of the study was to characterize the antifungal activity and synergistic potential of essential oil extracted from leaves of Citrus aurantium L. of North-Western Himalayas against Candida albicans.

Materials and methods: Citrus aurantium essential oil (CAEO) was extracted from leaves and characterized by GC-MS. The antifungal activity and synergistic potential of CAEO against C. albicans was studied by agar well diffusion, and broth microdilution assay. The anti-fungal potential of the phytoconstituents of CAEO was studied by in silico interaction with two fungal drug targets, N-myristoyl transferase (NMT) and Cytochrome P450 14 Alpha-sterol Demethylase (CYP51).

Results: CAEO exhibited strong antifungal activity against two strains of C. albicans, with fungicidal effect. The MIC of CAEO against C. albicans strains was 0.15 - 0.31 % (v/v). CAEO exhibited synergistic potential with fluconazole and amphotericin B against C. albicans and enhanced the antifungal efficacy of the clinical drugs by 7.7 to 333 folds. The GC-MS analysis of CAEO identified atleast ten compounds, with 2-β pinene, δ-3 Carene and D-limonene as the major compounds. In silico molecular docking of the three major phytocompounds of CAEO with NMT and CYP51 revealed their potential to interact with both targets. δ-3 Carene showed best binding (E_total of -131.13 kcal/mol) with NMT, while D-limonene exhibited highest binding energy (E_total of -175.23 kcal/mol) with CYP51. ADME/T analysis showed that 2-β pinene, δ-3 Carene and D-limonene exhibit drug likeliness and ideal toxicity profiles for their use as drug candidates.

Conclusions: Thus, the essential oil from leaves of C. aurantium and its phytocomponents can be used as sustainable and natural therapeutic to treat candidiasis as well as a resource to enhance the potency of clinical antibiotics, which have lost efficacy due to emergence of drug resistance in C. albicans.

Keywords: Candida albicans; Citrus aurantium; D-limonene; Molecular docking; Synergistic; Toxicity; essential oil; δ-3 Carene.