Multiparameter Optimization of <i> <i>Pseudomonas aeruginosa</i> </i> Elastase Inhibitors for Systemic Administration

Targeting the extracellular protease elastase (LasB) of the high-priority pathogen <i><i>Pseudomonas aeruginosa</i></i> is a promising strategy to develop second-generation, narrow-spectrum antibiotics with a novel mode of action. <i><i>P. aeruginosa</i></i> is responsible for a variety of infections, particularly of the lung. Herein, we report the structure-based optimization of a previously reported potent and selective phosphonate-based LasB inhibitor scaffold. Having improved the activity while maintaining high selectivity and favorable ADMET properties, we also demonstrate, for the first time within this scaffold, that intravenous administration leads to favorable lung retention. We could rationally align this with <i>in vitro</i> plasma protein binding. We further observed a link between physicochemical properties like logD_7.4 and protein binding, including surfactant proteins that can impair compound activity in the lung. This multiparameter optimization paves the way for the exploration of additional indications requiring systemic treatment, such as hospital-acquired or ventilator-associated pneumonia.