# Multiparameter Optimization of Pseudomonas aeruginosa Elastase Inhibitors for Systemic Administration

## TL;DR

This paper describes the development of optimized inhibitors for a key enzyme in a dangerous bacteria, with improved properties for treating lung infections.

## Contribution

The study introduces a multiparameter optimization of LasB inhibitors with systemic administration and lung retention capabilities.

## Key findings

- Optimized inhibitors show improved activity and selectivity with favorable ADMET properties.
- Intravenous administration leads to favorable lung retention for the first time in this scaffold.
- Physicochemical properties correlate with protein binding and lung activity.

## Abstract

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.