Ho Duy-Khiet, De Rossi Chiara, Loretz Brigitta, Murgia Xabier, Lehr Claus-Michael
HIPS-Helmholtz Institute for Pharmaceutical Research Saarland, HZI-Helmholtz Center for Infection Research, D-66123 Saarbrücken, Germany.
Department of Pharmacy, Saarland University, D-66123 Saarbrücken, Germany.
Pharmaceutics. 2020 Jul 22;12(8):691. doi: 10.3390/pharmaceutics12080691.
The search for novel therapeutics against pulmonary infections, in particular (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.
为应对日益增长的抗菌药物耐药性问题，针对肺部感染，尤其是铜绿假单胞菌（PA）生物被膜感染的新型治疗方法的研究一直十分活跃。尽管在药物发现和递送策略方面取得了诸多成果，但只有少数治疗方法进入了临床阶段。为了实现及时的临床前开发，制剂应具有高效、安全的特点，最重要的是易于生产。因此，与先进的药物递送系统相比，一种能增强治疗效果的已知活性成分的简单组合将是更优先的选择。在本研究中，我们提出了一种新型组合，即抗炎剂衣康酸（衣康酸盐，IA）与已获批的抗生素妥布霉素（Tob）或环丙沙星（Cipro）的组合。与单独使用妥布霉素相比，摩尔比为1:5的妥布霉素和衣康酸的组合使PA14野生型（wt）菌株中的生物被膜清除效果提高了约4倍。相比之下，衣康酸与环丙沙星的组合未观察到这种效果。随后关于衣康酸对细菌生长、绿脓菌素产生和妥布霉素生物被膜穿透影响的研究表明，与衣康酸络合可增强妥布霉素通过生物被膜的转运。我们建议将简单有效的妥布霉素：衣康酸组合用于PA生物被膜感染的先进临床前模型的进一步测试。
