Our findings demonstrate that: (1) PG-1 exhibits potent and resistance-resistant bactericidal activity against the virulent strain PCN033 in vitro; (2) it confers significant protective efficacy in a murine systemic infection model with an acceptable safety profile; and (3) the protective effect is mechanistically underpinned by the unique capacity of PG-1 to reprogram hyperactivated immune and metabolic pathways, particularly NF-κB and HIF-1 signaling, thereby reversing infection-induced immunopathology. This evidence concerns the gene NFKB1 and infection.