Monday, May 19, 2025
5/19/2025
Aerosol delivery of combinational therapeutics targeting deadly lung infections - Project Summary/Abstract Pulmonary infections caused by multidrug-resistant bacteria are extremely difficult to treat. Gram-negative `superbugs' are particularly worrisome in pulmonary infections and are often only susceptible to polymyxins. However, intravenous polymyxins have poor efficacy for pulmonary infections due to limited drug exposure in the airway. Inhaled polymyxins have been increasingly used in the clinic for the treatment of pulmonary infections; yet current inhalation therapies are empirical and have never been optimized using pharmacokinetics/pharmacodynamics/toxicodynamics approaches. No systematic evaluations have ever been conducted on the pulmonary toxicity of inhaled polymyxins. Furthermore, the currently used traditional jet nebulization has very low delivery efficiency (<15% of drug delivered to the lungs). Suboptimal use of inhaled polymyxins has caused unsatisfactory therapeutic efficacy, emergence of resistance, frequent adverse effects, and poor patient compliance. We have elucidated that polymyxin-induced pulmonary toxicity involves drug accumulation in human alveolar epithelial cells, particularly in mitochondria, which leads to oxidative stress, mitochondrial damage and apoptosis. Excitingly, we discovered that polymyxin combinations with aminoglycosides can significantly attenuate polymyxin-induced pulmonary toxicity, maximize antimicrobial activity and prevent resistance development. In this proposal, we will employ a multi-disciplinary approach to develop efficient powder aerosol delivery systems for these promising polymyxin combinations. The overarching hypothesis is that our optimized aerosol therapy of polymyxin combinations possesses superior delivery efficiency and PK/PD/TD to treat pulmonary infections; prevents bacterial resistance by synergistically inhibiting multiple key biochemical pathways; and minimizes toxicity in lung epithelial cells. The specific aims are: (1) To elucidate the mechanisms of attenuation of polymyxin-induced pulmonary toxicity by aminoglycosides using advanced imaging, CRISPR and transcriptomics; (2) To develop efficient aerosol delivery systems of polymyxin combinations using innovative manufacturing techniques; (3) To examine the tripartite relationships among human lung cells, Gram-negative pathogens, and superior polymyxin combinations using correlative multi-omics; and (4) To optimize the dosage regimens of superior inhaled polymyxin combination formulations using a machine learning-driven mechanism-based PK/PD/TD model. Our project responds in a timely manner to the recent National Action Plan for Combating Antibiotic-Resistant Bacteria (2020 – 2025).
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