Siderophore based molecular imaging of pulmonary infections

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PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is a progressive, debilitating respiratory condition with a clinical course that is punctuated by acute exacerbations (AECOPD) ranging from self-limited episodes to florid respiratory failure. AECOPD are most often precipitated by viral and/or bacterial infections. The bacterial organisms that commonly play pathogenic role in AECOPD are Pseudomonas, Klebsiella, Acinetobacter, and Enterobacter, and multidrug resistant Pseudomonas and Klebsiella pneumoniae are a common cause of secondary pneumonias in hospitalized patients with COPD. The change in color of sputum indicative of purulence that is often used as a surrogate marker for the presence of bacterial infection is a late, inconsistent, nonspecific and insensitive biomarker; it cannot distinguish between viral and bacterial infection, and many patients with AECOPD do not produce sputum at all. The availability of a targeted, pathogen-specific and sensitive imaging modality that could detect bacteria in the lower airways and differentiation bacterial from viral infection non-invasively would advance our understanding of AECOPD and facilitate development of preemptive treatment paradigms. In this proposal, we intend on using these unique bacterial membrane transporters on bacteria, and their distinct metallophores as PET reporter probes to localize and identify pathogenic live bacteria in AECOPD. We will also evaluate the specificity and sensitivity of the robes in identifying the bacteria in co- infection models with influenza virus (H3N2). We will further evaluate the responsiveness of the PET imaging probe and modality to different antibiotics, against several clinical isolates of K. pneumoniae and P. aeruginosa. If successful, the probes would be able to assist with identifying subclinical bacterial colonization of in patients with AECOPD, to determine if the bacteria that are ultimately responsible for the infection are the same strains that was found to be colonizing. This project will lay the foundation for a new technology platform that will open avenues to explore the possibility of using the diverse array of metallophores as contrast agents for imaging the entire repertoire of pathogenic infections.