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journal article·2025-04Open access

Dipeptidic Phosphonates: Potent Inhibitors of Pseudomonas aeruginosa Elastase B Showing Efficacy in a Murine Keratitis Model

Alexander F. Kiefer, Christian Schütz, Colya N. Englisch, Dominik Kolling, Samira Speicher, Andreas M. Kany, Roya Shafiei, Noran A. Wadood, Ahmad Aljohmani, Niklas Wirschem, Ravindra P. Jumde, Andreas Klein, Asfandyar Sikandar, Yu‐Mi Park, Gabriela Krasteva‐Christ, Daniela Yildiz, Ahmed S. Abdelsamie, Katharina Rox, Jesko Köhnke, Rolf Müller, Markus Bischoff, Jörg Haupenthal, Anna K. H. Hirsch

Advanced Science· Volume 12· Issue 14
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Source abstract

Abstract

Abstract The ubiquitous opportunistic pathogen Pseudomonas aeruginosa is responsible for severe infections and notoriously known for acquiring antimicrobial resistance. Inhibiting the bacterium's extracellular elastase, LasB – a zinc‐dependent protease – presents a promising strategy to mitigate its virulence. Within this medicinal chemistry–driven hit‐to‐lead optimization campaign, a new series of highly potent dipeptidic phosphonates is designed and synthesized following a structure–based drug‐discovery approach. In vitro and in vivo evaluation reveal beneficial pharmacokinetic profiles, excellent selectivity over human off‐targets and good tolerability in murine toxicity studies. Ultimately, the scaffold presented herein demonstrates promising in vivo efficacy in a murine Pseudomonas aeruginosa keratitis model in combination with the antibiotic meropenem.
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Research context

OpenAlex topics: Antibiotic Resistance in Bacteria · Antimicrobial Peptides and Activities · Click Chemistry and Applications

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) Campus E8.1 66123 Saarbrücken Germany

Helmholtz Centre for Infection Research (HZI) Inhoffenstraße 7 38124 Braunschweig Germany

German Center for Infection Research (DZIF) Inhoffenstraße 7 38124 Braunschweig Germany

PharmaScienceHub (PSH) Campus A2.3 66123 Saarbrücken Germany

Institute for Medical Microbiology and Hygiene Saarland University Kirrbergerstraße 100 66421 Homburg/Saar Germany

Institute for Food Chemistry Callinstraße 5 30167 Hannover Germany

Department of Pharmacy Saarland University Campus E8.1 66123 Saarbrücken Germany

Institute of Anatomy and Cell Biology Saarland University Kirrbergerstraße 100 66421 Homburg/Saar Germany

Institute of Experimental and Clinical Pharmacology and Toxicology PZMS ZHMB Saarland University Kirrbergerstraße 100 66421 Homburg/Saar Germany

Department of Chemical Biology Helmholtz Centre for Infection Research (HZI) Inhoffenstraße 7 38124 Braunschweig Germany

Funding

Deutsches Zentrum für Infektionsforschung · Deutsche Forschungsgemeinschaft

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