Optimization of a novel antimicrobial for pulmonary delivery to fight respiratory infections

Title: Optimization of a novel antimicrobial for pulmonary delivery to fight respiratory infections Antibiotic resistance (AR) has reached alarming levels in the US and other parts of the world in recent decades. Increased infections with AR bacterial pathogens result in increased healthcare costs and a decline in positive clinical outcomes. Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species together are known as ESKAPE pathogens because they are the six top-priority dangerous 'superbugs' easily generate resistance and require the most urgent attention for novel antibiotics. Multidrug-resistant (MDR) ESKAPE infections are emerging causes of AR infections associated with high morbidity and mortality rates. Despite tremendous efforts, the lack of efficacious new antimicrobials is an enormous concern because of the potential threats posed by emerging/re-emerging AR pathogens to public health and global healthcare. It's a significant medical challenge to lack novel, effective antibiotics to treat AR bacterial infections, and our long-term objective is to develop novel antimicrobials to combat urgent AR bacterial infections efficiently. We have recently developed a natural airway host defense molecule SPLUNC1 inspired lead antimicrobial peptide, A4-X7, that has enhanced stability, potency, and safety, making it an ideal therapeutic candidate for treating a broad range of AR bacterial respiratory infections. In this application, we hypothesize that formulating A4-X7 for aerosolized pulmonary delivery is an effective and well- tolerated novel approach to successfully treating AR bacterial respiratory infections. Our proposed studies will prepare, characterize, and evaluate the antimicrobial and antibiofilm activities of formulated A4-X7 for aerosolized pulmonary delivery. We will then determine aerosol dispersion performance, lung deposition, pharmacokinetics, pharmacodynamics, and inhalation aerosol safety as liquid aerosols and inhaled dry powders of formulated A4-X7. By focusing on developing novel A4-X7 for targeted pulmonary delivery, our study will provide an alternative and effective treatment to fight MDR ESKAPE respiratory infections.