An integrated systems biology approach establishes arginine biosynthesis as a metabolic weakness in Candida albicans during host infection

Candida albicans ( CAL ) , one of the leading causes of fungal infections affecting nearly 70% of the population, pose a significant global health threat. With the emergence of drug-resistant strains, the mortality rates have reached a staggering 63.6% in severe cases, complicating treatment options and demanding the discovery of novel therapeutic targets. To address this pressing need, the study employed an innovative multidisciplinary approach to elucidate the metabolic pathways that enable CAL to switch from a commensal to a virulent state. Condition-specific genome-scale metabolic models (GSMMs), along with a novel integrated host-CAL model developed in this study, highlighted the central role of arginine (Arg) metabolism and uncovered ALT1 , an arginine biosynthesis enzyme, as a critical metabolic vulnerability in CAL virulence. Heightened expression of arginine biosynthesis genes in the presence of host indicated that increased arginine synthesis mainly occurs through proline intermediates during host interaction. Significantly impaired virulence and in vivo pathogenicity of ALT1 -deleted CAL highlighted the potential of disrupting arginine metabolism as an alternative strategy to combat antifungal resistance and underscored the power of integrating systems biology with experimental approaches in identifying new therapeutic targets.