The search for novel therapeutics against pulmonary infections, in particular Pseudomonas aeruginosa (PA) biofilm infections, has been intense to deal with the emergent rise of antimicrobial resistance. Despite the numerous achievements in drug discovery and delivery strategies, only a limited number of therapeutics reach the clinic. To allow a timely preclinical development, a formulation should be highly effective, safe, and most importantly facile to produce. Thus, a simple combination of known actives that enhances the therapeutic efficacy would be a preferential choice compared to advanced drug delivery systems. In this study, we propose a novel combination of an anti-inflammatory agent—itaconic acid (itaconate, IA)—and an approved antibiotic—tobramycin (Tob) or ciprofloxacin (Cipro). The combination of Tob and IA at a molar ratio of 1:5 increased the biofilm eradicating efficacy in the strain PA14 wild type (wt) by ~4-fold compared to Tob alone. In contrast, such effect was not observed for the combination of IA with Cipro. Subsequent studies on the influence of IA on bacterial growth, pyocyanin production, and Tob biofilm penetration indicated that complexation with IA enhanced the transport of Tob through the biofilm. We recommend the simple and effective combination of Tob:IA for further testing in advanced preclinical models of PA biofilm infections.

中文翻译：

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衣康酸提高妥布霉素对抗铜绿假单胞菌生物膜的功效。


针对肺部感染，特别是铜绿假单胞菌(PA) 生物膜感染的新疗法的研究一直在紧张进行，以应对抗菌素耐药性的突然上升。尽管在药物发现和递送策略方面取得了众多成就，但只有有限数量的治疗方法到达了临床。为了能够及时进行临床前开发，制剂应该高效、安全，最重要的是易于生产。因此，与先进的药物递送系统相比，增强治疗功效的已知活性物质的简单组合将是优先选择。在这项研究中，我们提出了一种抗炎剂衣康酸（衣康酸，IA）和批准的抗生素妥布霉素（Tob）或环丙沙星（Cipro）的新型组合。与单独使用 Tob 相比，以 1:5 摩尔比组合使用 Tob 和 IA 可使 PA14 野生型 (wt) 菌株的生物膜根除功效提高约 4 倍。相反，IA 与 Cipro 的组合则没有观察到这种效果。随后关于 IA 对细菌生长、绿脓蛋白产生和 Tob 生物膜渗透的影响的研究表明，与 IA 的络合增强了 Tob 通过生物膜的转运。我们建议简单有效的 Tob:IA 组合在 PA 生物膜感染的高级临床前模型中进行进一步测试。