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<sub>7.4</sub> 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.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2026-02-05
DOI
https://doi.org/10.1021/acs.jmedchem.5c02788
Primary Topic
Microbial Natural Products and Biosynthesis
Type
article
Field-Weighted Citation Impact
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article

Multiparameter Optimization of Pseudomonas aeruginosa Elastase Inhibitors for Systemic Administration

Katharina Mundry, Ahmed S. Abdelsamie, Dominik Kolling, Brigitta Loretz et al.
Journal of Medicinal Chemistry
Microbial Natural Products and Biosynthesis
article

Multiparameter Optimization of Pseudomonas aeruginosa Elastase Inhibitors for Systemic Administration

Katharina Mundry, Ahmed S. Abdelsamie, Dominik Kolling, Brigitta Loretz, Katharina Rox, Jelena Konstantinović, Christian Schütz, Yu Mi Park, Anna K. H. Hirsch, Mélodie Bouté, Jesko Koehnke, Richard Müller, Roya Shafiei, Samira Speicher, Jean-Michel Sallenave, Jörg Haupenthal, Andreas M. Kany, Claus-Michael Lehr, Andreas Klein
article en

Abstract

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<sub>7.4</sub> 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.

Journal of Medicinal ChemistryVol. 69(4)
Inserm (FR), Université Paris Cité (FR), Chembio (United States) (US), Bioscience Research (US), German Center for Infection Research (DE), Helmholtz Centre for Infection Research (DE), Helmholtz Center for Information Security (DE), Centre de Recherche sur l'Inflammation (FR), Helmholtz Institute for Pharmaceutical Research Saarland (DE), Hôpital Bichat-Claude-Bernard (FR), Physiopathologie et Epidémiologie des Maladies Respiratoires (FR)
Good health and well-being
Openalex Percentile: Top 64%
Microbial Natural Products and Biosynthesis
DOIOpen Access PDFOpenAlex
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