Multiparameter Optimization of Pseudomonas aeruginosa Elastase Inhibitors for Systemic Administration

Targeting the extracellular protease elastase (LasB)
of the high-priority
pathogen Pseudomonas aeruginosa is a promising strategy to develop second-generation, narrow-spectrum
antibiotics with a novel mode of action. P.
aeruginosa 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 in vitro plasma protein binding. We further
observed a link between physicochemical properties like logD7.4 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.