Natural Compound–Mediated SUMOylation Rewires Host Immunity Against <i>Klebsiella pneumoniae</i>

Abstract Klebsiella pneumoniae is a major cause of multidrug-resistant and hypervirulent infections worldwide, highlighting the urgent need for host-directed therapeutic strategies that complement conventional antibiotics. Emerging evidence suggests that K. pneumoniae promotes intracellular persistence by suppressing host SUMOylation, a reversible post-translational modification that regulates protein stability, cellular signaling, and innate immune response. This decrease in SUMOylation perturbs NF-κB signaling, leading to dysregulation of inflammation that promotes bacterial survival, rather than effective immune clearance. Clove Bud Oil (CBO), a natural product derived from Syzygium aromaticum , has previously been shown to possess anti-virulence as well as immunomodulatory properties. In this regard, we investigated the capability of CBO to restore host SUMOylation and enhance innate immune response during infection with classical as well as hypervirulent K. pneumoniae . In macrophages, classical and hypervirulent K. pneumoniae impaired global host SUMOylation, disrupting IKKβ–RelA/NF-κB signalling and uncoupling inflammatory regulation from effective antimicrobial defense to facilitate intracellular persistence. CBO restored SUMOylation-dependent immune homeostasis by attenuating sustained IKKβ phosphorylation and degradation, thereby constraining aberrant RelA nuclear translocation, rebalancing pro-inflammatory cytokine responses, and restricting intracellular bacterial survival. These findings demonstrate that restoration of host SUMOylation acts as a key driver of the immunomodulatory activity of CBO, leading to coordinated innate immune responses and enhanced intracellular bacterial clearance. Collectively, our study identifies host SUMOylation as a critical pathway targeted during K. pneumoniae infection and highlights restoration of SUMOylation-mediated immune homeostasis as a promising host-directed therapeutic strategy against multidrug-resistant and hypervirulent K. pneumoniae . Author Summary Antibiotic-resistant Klebsiella pneumoniae has become a major global health threat, making it increasingly important to identify alternate strategies to treat infections that do not rely solely on antibiotics. In this study, we investigated how Klebsiella pneumoniae interferes with host immune defenses. Our findings demonstrate that the pathogen disrupts SUMOylation, a key cellular process involved in coordinating balanced immune responses. Impaired SUMOylation dysregulates immune signaling, thereby promoting bacterial survival within host cells. We further examined whether clove bud oil (CBO), a natural product with established biological activity, could restore SUMOylation-mediated immune regulation. Our results show that clove bud oil re-established host SUMOylation, normalized immune signaling, reduced excessive inflammatory responses, and improved the ability of immune cells to eliminate both classical and hypervirulent strains of K. pneumoniae . These findings suggest that the beneficial effects of clove bud oil arise not only from its antimicrobial properties but also from its ability to modulate the host immune response by restoring normal cellular regulation. Our study identifies host SUMOylation as a promising therapeutic target and provides evidence that strengthening the body’s own immune defenses may offer an alternative strategy to combat multidrug-resistant bacterial infections.