Background and Purpose: The increment in fungal infections, particularly due to Candida
species, is alarming due to the emergence of multidrug resistance (MDR). Hence, the identification of novel drug targets to circumvent the problem of MDR requires immediate attention. The metabolic pathway, such as glyoxylate cycle
(GC), which utilizes key enzymes (isocitrate lyase [ICL] and malate synthase [MLS]), enables C. albicans to adapt under glucose-deficient conditions. This study uncovers the effect of GC disruption on the major MDR mechanisms of C. albicans as a human pathogenic fungus. Materials and Methods: For the purpose of the study, efflux pump activity was assessed by phenotypic susceptibilities in the presence of substrates rhodamine ۶G (R۶G) and Nile red, along with R۶G extracellular concentration (۵۲۷ nm). In addition, ergosterol
content was estimated by the alcoholic potassium hydroxide hydrolysis method. The estimation of chitin was also accomplished by the absorbance (۵۲۰ nm) of glucosamine released by acid hydrolysis. Results: The results revealed that the disruption of ICL enzyme gene (Δicl۱) led to the impairment of the efflux activity of multidrug transporters belonging to the ATP-binding cassette superfamily. It was further shown that Δicl۱ mutant exhibited diminished ergosterol
and chitin contents. In addition, all abrogated phenotypes could be rescued in the reverting strain of Δicl۱ mutant. Conclusion: Based on the findings, the disruption of GC affected efflux activity and the synthesis of ergosterol
and chitin. The present study for the first time revealed that metabolic fitness was associated with functional drug efflux, ergosterol
and chitin biosynthesis and validated GC as an antifungal target. However, further studies are needed to comprehend and exploit this therapeutic opportunity.