Antibiotic Alternative: Purinergic Signaling Modulators on Macrophage Internalization of Klebsiella Pneumoniae

Abstract

Antimicrobial resistance (AMR) is a significant global health crisis, and there is an urgency for alternative therapeutic strategies that reduce the use of traditional antibiotics. In this study, I explored the efficacy of purinergic signaling modulators in enhancing (and diminishing) the internalization of Klebsiella pneumoniae (KP-ATCC70063) by macrophages. Klebsiella pneumoniae is a pneumonia-causing pathogen implicated as one of the leading causes of hospitalization in the US and the most common cause of death by infection. By employing an internalization assay, I quantified macrophage bacterial uptake via viable internalized cell counts (VCC) in CFU/mL. The results showed that CGS, an adenosine A2A receptor agonist, significantly increased bacterial internalization by 0.0645% (95% CI [0.0285, 0.1005], p = 0.00299), suggesting its potential to bolster macrophage efficacy in phagocytosis. Conversely, other modulators (ZM, AntA2B, ADO, and INO) decreased bacterial internalization, with reductions ranging from -0.0704% to -0.0741% (p-values ranging from 0.00142 to 0.00187), which could also be advantageous in managing excessive inflammatory responses in autoimmune diseases or chronic infections, for instance. I also validated previous findings in a second experiment with a direct bacterial assay which demonstrated that these modulators did not directly affect bacterial viability, showing that purinergic signaling modulators work by modulating host cell functions rather than exerting direct antimicrobial effects on bacteria. This study highlights the potential of purinergic signaling modulators for use in tandem with macrophage therapy as an alternative for mitigating antibiotic overuse and ultimately combating AMR.