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

mBio, American Society for Microbiology

16 June 2026 doi.org/10.1128/mbio.00618-26

Joel Abraham, Aswathy C. Sagilkumar, Himani Dhyani, Charmi M. Panchal, Shaheena Aziz, M. K. Priyadatha, Aan Ruth, Keerthana Bhaskaran, Sivakumar Krishnankutty Chandrika, S. Shaima, Rosemol Varghese, Ayyanraj Neeravi, Balaji Veeraragavan, Nagarjun Narayanaswamy, Sandhya Ganesan, Karthik Subramanian

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.