Guaiazulene and aureusidin inhibit metabolic adaptability and virulence in <i>Candida albicans</i> by targeting the glyoxylate cycle under alternative carbon conditions

Several Candida species such as C. albicans and C. auris have emerged as formidable multidrug-resistant pathogens, posing significant challenges to global healthcare. C. albicans can rapidly adapt its metabolism under nutrient-limited conditions, such as low-carbon environments, leading to virulence and drug resistance. Therefore, identifying novel compounds that can disrupt this metabolic adaptability is crucial for developing effective therapeutic strategies against this elusive pathogen. In this study, we first employed an in-silico dynamics approach to investigate the inhibitory effects of guaiazulene and aureusidin on C. albicans metabolic adaptability and virulence. By employing molecular docking and molecular dynamics simulations, we demonstrated that these compounds strongly interacted with crucial enzymes involved in the glyoxylate cycle, impairing their catalytic functions. Guaiazulene exhibited the highest binding affinity for malate synthase and isocitrate lyase, with a docking score of −8.5 and −9.3 kcal/mol, respectively. The ADME properties of these molecules were also examined to evaluate the pharmacological parameters. Furthermore, we investigated the impact of guaiazulene and aureusidin on C. albicans growth and biofilm formation. Our findings indicated that the targeting the glyoxylate cycle represents a promising strategy to counteract the metabolic adaptability of C. albicans and enhance the efficacy of antifungal agents.