Toll-like receptor 5 (TLR5) signaling plays a key role in antibacterial defenses. We previously showed that respiratory administration of flagellin, a potent TLR5 agonist, in combination with amoxicillin improves the treatment of primary pneumonia or superinfection caused by amoxicillin-sensitive or -resistant Streptococcus pneumoniae. Here, the impact of adjunct flagellin therapy on antibiotic dose/regimen and the selection of antibiotic-resistant S. pneumoniae was investigated using superinfection with isogenic antibiotic-sensitive and -resistant bacteria and population dynamics analysis. Our findings demonstrate that flagellin allows for a 200-fold reduction in the antibiotic dose, achieving the same therapeutic effect observed with antibiotic alone. Adjunct treatment also reduced the selection of antibiotic-resistant bacteria in contrast to the antibiotic monotherapy. Finally, we developed a mathematical model that captured the population dynamics and estimated a 20-fold enhancement immune-modulatory factor on bacterial clearance. This work paves the way for the development of host-directed therapy and refinement of treatment by modeling.

中文翻译：

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肺炎球菌重复感染期间触发 Toll 样受体 5 信号传导可防止抗生素耐药性的选择

Toll 样受体 5 (TLR5) 信号传导在抗菌防御中发挥关键作用。我们之前表明，将鞭毛蛋白（一种有效的 TLR5 激动剂）与阿莫西林联合呼吸道给药可改善对阿莫西林敏感或耐药的肺炎链球菌引起的原发性肺炎或二重感染的治疗。在这里，利用同基因抗生素敏感和耐药细菌的重复感染和种群动态分析，研究了辅助鞭毛蛋白治疗对抗生素剂量/方案和耐药肺炎链球菌选择的影响。我们的研究结果表明，鞭毛蛋白可以将抗生素剂量减少 200 倍，达到与单独使用抗生素相同的治疗效果。与抗生素单一疗法相比，辅助治疗还减少了抗生素耐药细菌的选择。最后，我们开发了一个数学模型，可以捕捉种群动态，并估计细菌清除率增强 20 倍的免疫调节因子。这项工作为宿主导向治疗的发展和通过建模改进治疗铺平了道路。