Sorafenib, a clinical kinase inhibitor, attenuates <i>Streptococcus pneumoniae</i> pathogenesis and reduces disease progression <i>in vivo</i>

ABSTRACT Streptococcus pneumoniae is an opportunistic respiratory commensal bacterium and leading cause of pneumonia, meningitis, and sepsis, resulting in over a million deaths annually, particularly in children aged under 5. The rapid spread of macrolide-resistant strains led the WHO to designate S. pneumoniae as a priority pathogen that urgently requires alternative therapeutic strategies. Here, we identified the FDA-approved cancer drug sorafenib to show a dose-dependent, broad-spectrum efficacy against many pneumococcal serotypes, including multidrug-resistant clinical strains. In silico screening and molecular dynamics simulations indicated potential interaction with the catalytic cleft of the pneumococcal serine/threonine kinase StkP, a central regulator of cell division and peptidoglycan synthesis. In vitro kinase assays using purified recombinant StkP kinase domain and p-Thr-specific immunoblotting revealed dose-dependent inhibition of kinase activity by sorafenib in pneumococci. Ectopic expression of StkP partially rescued growth inhibition by sorafenib, and the direct interaction was assessed by isothermal titration calorimetry, suggesting StkP as one of the potential targets in S. pneumoniae . Sorafenib-treated bacteria showed abnormal morphology, increased membrane permeability, enhanced complement C3 deposition, and reduced adherence and invasion into lung epithelial cells without significant host cytotoxicity. Serial passaging of bacteria in vitro with sorafenib suggested low resistance potential. In vivo , sorafenib administration at 10% of the clinically relevant dose delayed mortality and significantly reduced bacterial burden in a murine pneumonia model, supporting its further preclinical development for therapeutic intervention. IMPORTANCE Streptococcus pneumoniae , a WHO priority pathogen and causative of pneumonia, meningitis, and sepsis worldwide, has developed resistance to several commonly used antibiotics, limiting available treatment options. In this study, we show that sorafenib, a drug currently approved for cancer treatment, can also inhibit the growth and disease-causing ability of S. pneumoniae , including clinical strains. Our findings reveal that sorafenib interferes with a key bacterial regulatory enzyme that controls cell division and cell wall formation, exposing a previously underexplored vulnerability in this pathogen. Because sorafenib is already clinically approved, this work highlights the potential of drug repurposing as a faster route to identify new antimicrobial therapies. More broadly, our results demonstrate that bacterial kinases represent promising targets for developing next-generation treatments against key bacterial pathogens.