Synergy between immune system and antibiotics drives infection control in mice

Background: Antibiotics and host immunity are traditionally viewed as independent defenses, with antibiotics reducing bacterial load to levels manageable by the immune system. Modeling studies, however, predict that synergy between these defenses is critical for infection control, but this has not been experimentally verified. Methods: wound infection model in immunocompetent (C57BL/6) and immunocompromised (NSG) mice treated with systemic tobramycin. Results: In C57BL/6 mice, tobramycin-mediated bacterial killing increased pathogen-associated molecular patterns (PAMPs) - namely lipopolysaccharide (LPS) - which in turn amplified local inflammation, enhancing antibiotic efficacy in a manner largely dependent on neutrophils. In contrast, NSG mice failed to potentiate tobramycin bacterial killing to increase PAMPs and mount Tobramycin-induced boost in immune activation, resulting in reduced infection control. Importantly, topical PAMPs (LPS and N-formyl-methionyl-leucyl-phenylalanine (fMLP)) restored immune activation and improved infection control in NSG mice in a manner that was also dependent on neutrophil's function. Conclusion: These findings provide direct experimental evidence that antibiotic efficacy requires synergy with host immunity. They highlight the therapeutic potential of augmenting innate immune activation to improve infection outcomes, particularly in immunocompromised patients.