Advancing innovative therapies against pandrug-resistant Gram-negative superbugs

世界卫生组织（WHO）最近列出了革兰氏阴性“超级细菌”肺炎克雷伯氏菌， 铜绿假单胞菌和鲍曼不动杆菌为最关键的致病菌，其中以 威胁人类健康。由于新型抗生素的开发进展缓慢，多粘菌素经常被使用 作为革兰氏阴性菌感染的最后一线治疗;然而，临床研究表明， 肠外多粘菌素治疗革兰氏阴性肺部感染的效果令人失望， 药物暴露于气道表面的感染部位和剂量限制性肾毒性。更令人担忧 是多粘菌素单一疗法诱导的多粘菌素抗性的发展。一个有前途的 治疗革兰氏阴性肺部感染的策略是直接递送协同多粘菌素 在气道表面的感染部位的组合。然而，传统的雾化具有低递送 更糟糕的是，目前的甲磺酸粘杆菌素（CMS）雾化疗法是经验性的， 从未使用药代动力学/药效学/毒理学（PK/PD/TD）进行系统优化。 本项目的总体目标是开发新的脂质体疗法的组合抗生素使用 创新的喷雾冷冻干燥粉末生产技术，尖端的成像，系统药理学和 基于机制的药代动力学/药效学/毒理学（PK/PD/TD）建模。具体 目的是：（1）使用创新的喷雾-冷冻-喷雾-喷雾-冷冻-喷雾-冷冻-喷雾 干燥工艺;（2）确定制剂的体外药效学;（3）阐明处置 多粘菌素组合制剂在气道中的作用及其机制 使用系统药理学评估潜在的肺毒性;（4）应用基于机制的PK/PD/TD 建模以优化啮齿动物肺部感染模型中的上级脂质体制剂的给药方案。 为了应对新出现的全球抗菌药物危机，我们必须以新的方式超越“超级细菌”的进化 战略布局随着开发针对MDR革兰氏阴性病原体的新抗生素的令人失望的进展， 我们的创新多学科项目解决了NIAID的战略方法“扩大临床 抗菌药物的效用-优化现有药物的使用和联合治疗， 出现耐药性并将毒性降至最低”。我们工作的成功将对世界产生更广泛的影响。 美国和全球健康为平台，可以很容易地应用于开发其他上级新疗法， 呼吸道感染，如肺结核。

The World Health Organization (WHO) has recently listed Gram-negative ‘superbugs’ Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii as the most critical pathogens, which are the greatest threat to human health. Due to the slow progress in development of novel antibiotics, polymyxins are often used as the last-line therapy against Gram-negative infections; however, clinical studies have shown that the efficacy of parenteral polymyxins is disappointing for the treatment of Gram-negative lung infections due to very low exposure of the drug to the infection site at the airway surface and dose-limiting kidney toxicity. More worrying is the development of polymyxin resistance induced by the polymyxin monotherapy. One of the promising strategies for the treatment of Gram-negative lung infections is direct delivery of synergistic polymyxin combinations to the infection sites at the airway surface. However, conventional nebulization has low delivery efficiency; even worse, current colistin methanesulfonate (CMS) nebulization therapies are empirical and have never been systematically optimized using pharmacokinetic/pharmacodynamic/toxicodynamic (PK/PD/TD). The overall aim of this project is to develop novel liposomal therapies for combinational antibiotics using innovative spray-freeze-drying powder production technology, cutting-edge imaging, systems pharmacology and mechanism-based pharmacokinetic/pharmacodynamic/toxicodynamic (PK/PD/TD) modeling. The Specific Aims are: (1) to develop novel liposomal formulations of polymyxin combinations using innovative spray-freeze- drying technology; (2) to determine in vitro pharmacodynamics of the formulations; (3) to elucidate the disposition of polymyxin combinations from the formulations in the airway using cutting-edge imaging and the mechanisms of potential pulmonary toxicities using systems pharmacology; (4) to apply mechanism-based PK/PD/TD modeling to optimizing dosage regimens of the superior liposomal formulation in rodent lung infection models. To combat the emergent global antimicrobial crisis, we must outpace the evolution of ‘superbugs’ by novel strategies. With the disappointing progress in developing new antibiotic against MDR Gram-negative pathogens, our innovative multi-disciplinary project addresses NIAID’s strategic approach “extending the clinical utility of antibacterial drugs̸optimizing use of existing drugs and combination therapies to suppress emergence of resistance and minimize toxicity”. The success of our work will have a broader impact to the USA and global health as the platform can be readily applied to develop superior new therapies for other respiratory infections such as pulmonary tuberculosis.