Berkland Pilot Project Summary

The pulmonary system is a common entry point for pathogens, unfortunately treating lung infections via oral or IV antibiotics can be challenging due to poor penetration into infected lung tissues, rapid systemic elimination of the therapy, and dose-limiting side effects. Inhaling novel antibiotics designed to persist in the lung compartment after inhalation may dramatically improve efficacy, minimize systemic side effects, allow for the delivery of much higher doses, and potentially eliminate the need for IV administration. Designing novel antibiotics for inhalation represents an untapped scheme, which we propose to advance though rational antibiotic design and a novel screening approach. Imipenem was selected as a core antibiotic structure due to its small size, potency against B. pseudomallei and lone carboxylic acid handle for modification. The literature and our experience indicates an increase in molecular size as well as structures that are hydrophilic (lung fluid retention) or hydrophobic (membrane retention), cleavable (prodrug) or not, offer promise and will be explored. We will synthesize this diverse chemical library and screen for minimum inhibitory concentration (MIC) in B. thailandensis (a surrogate for B. pseudomallei) and for retention in an in vitro lung compartment model. We hypothesize imipenem derivatives larger than 600 Da with a LogP higher than 3 will exhibit maximum retention in the lung compartment model. We propose two Specific Aims:

Specific Aim #1: Design and synthesize derivatives of imipenem to improve lung retention after inhalation.

Specific Aim #2: Identify antibiotic activity and permeability through model lung epithelium.

We expect this Pilot Project will yield multiple imipenem derivatives that can ultimately be tested by our collaborators using mice infected by inhalation exposure to B. pseudomallei.