Thymol Attenuates Klebsiella pneumoniae Induced Lung Injury via Modulation of Peroxidase-Driven Oxidative Stress and Host-Pathogen Interactions: In Vivo and In Silico Insights.

Klebsiella pneumoniae pneumonia drives excessive inflammatory and oxidative responses that culminate in acute lung injury (ALI) and impaired bacterial clearance. Effective therapies capable of restoring host-pathogen balance remain limited, particularly in the context of multidrug-resistant strains. This study investigated the therapeutic efficacy of thymol in a murine model of K. pneumoniae-induced ALI. Oral thymol (5-20 mg/kg) markedly reduced lung injury, suppressed leukocyte infiltration, improved pulmonary histoarchitecture, and significantly enhanced bacterial clearance. Thymol reshaped systemic and local immune responses by decreasing tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP), increasing interleukin-10 (IL-10), and limiting macrophage and granulocyte recruitment. Mechanistically, thymol attenuated heme peroxidase-driven oxidative stress, as evidenced by reduced myeloperoxidase (MPO) and eosinophil peroxidase (EPO) activities, decreased malondialdehyde (MDA), hydrogen peroxide (H2O2), and nitric oxide (NO), along with restoration of catalase activity and glutathione levels. Complementary in silico docking predicted stable interactions of thymol with MPO and EPO, as well as essential bacterial metabolic enzymes, including deoxy-D-xylulose-5-phosphate synthase (DXS), acetolactate synthase (ALS), and dihydrodipicolinate synthase (DHDPS). Collectively, these findings suggest that thymol may act as a multi-target bioactive compound capable of modulating host inflammatory and redox pathways while potentially impairing bacterial metabolic fitness, thereby mitigating pneumonia-associated ALI.