Metabolic Adaptation via Glycolysis and Iron Acquisition Drives Klebsiella pneumoniae–Induced Intraocular Inflammation and Visual Impairment

Klebsiella pneumoniae is a major cause of endogenous endophthalmitis, a rapidly progressing intraocular infection associated with severe inflammation and vision loss. The vitreous body presents a hypoxic and iron-restricted environment, yet the bacterial metabolic adaptations that enable persistence in this niche remain largely unknown. Here, we show that K. pneumoniae undergoes metabolic reprogramming to facilitate intraocular survival, characterized by enhanced glycolysis and siderophore-mediated iron acquisition. Proteomic profiling under vitreous-mimicking conditions revealed significant upregulation of PfkA, PykF, and EntB. Targeted deletion of these genes impaired bacterial growth under hypoxia and iron limitation, and significantly reduced intraocular colonization, proinflammatory cytokine production, and visual impairment in a murine model. Double mutants lacking both glycolytic and iron acquisition pathways were nearly avirulent. Correspondingly, infected eyes exhibited lower levels of lactate and iron, reflecting reduced bacterial metabolic activity. These findings establish glycolysis and iron acquisition as critical determinants of K. pneumoniae virulence in the eye and provide insight into the metabolic strategies underpinning bacterial persistence in nutrient-limited host environments.