Introduction: Streptococcus pneumoniae (S. pneumoniae) is a commensal pathogen of the nasopharynx and one of the leading causes of bacterial death in children under the age of five. Especially prior infection with respiratory viruses like influenza A viruses is known to pave the way for secondary bacterial infection with severe outcome. S. pneumoniae displays high genetic plasticity allowing fast adaptation to antibacterial compounds and spread of resistances within and among species. The worldwide emergence of antibiotic resistance rates further dramatizes the clinical situation and presents a major threat to the global health system underscoring the pressing need for innovative solutions to replace or at least reduce the use of currently available antibiotics.

Goals: Zapnometinib, a compound with antiviral and antibacterial properties, is a promising candidate to combat both viral and bacterial infections. Here, we investigate the antibacterial activity of Zapnometinib against S. pneumoniae and analyze its interaction with commonly used antibiotics.

Materials & Methods: Besides EC50 determination of zapnometinib against S. pneumoniae, standard MIC assays were performed with different antibiotics. To further analyze drug interactions, we tested a diagonal synergy method that is derived from the checkerboard assay and allows a fast and easy screening for additivity or synergism.

Results: Zapnometinib exhibits remarkable antibacterial activity against S. pneumoniae, with an effective concentration 50% of 5 µM in vitro. Moreover, pretreatment of S. pneumoniae with zapnometinib reduces the minimal inhibitory concentration of various antibiotics potentially sensitizing the bacteria for antibiotic treatment. Interestingly, combination therapy with Penicillin-G resulted in a drug interaction score of 0.8, which corresponds to a synergistic effect.

Summary: Our initial findings on the promising interaction of zapnometinib with common antibiotics highlight its potential future importance for the treatment of co-infections and the fight against increasing antimicrobial resistance.