Dipeptidic Phosphonates: Potent Inhibitors of <i>Pseudomonas aeruginosa</i> Elastase B Showing Efficacy in a Murine Keratitis Model
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.
Authors
- Ahmed S. Abdelsamie (ORCID: https://orcid.org/0000-0002-5326-4400)
- Colya N. Englisch (ORCID: https://orcid.org/0000-0001-6746-3681)
- Andreas Klein (ORCID: https://orcid.org/0000-0001-8075-3480)
- Dominik Kolling (ORCID: https://orcid.org/0009-0005-1365-3128)
- Markus Bischoff (ORCID: https://orcid.org/0000-0001-6734-2732)
- Asfandyar Sikandar (ORCID: https://orcid.org/0000-0002-6566-4022)
- Katharina Rox (ORCID: https://orcid.org/0000-0002-8020-1384)
- Ahmad Aljohmani (ORCID: https://orcid.org/0000-0003-0982-3583)
- Ravindra P. Jumde (ORCID: https://orcid.org/0000-0002-2674-9605)
- Andreas M. Kany (ORCID: https://orcid.org/0000-0001-7580-3658)
- Noran Abdel Wadood (ORCID: https://orcid.org/0000-0001-6108-1797)
- Daniela Yildiz (ORCID: https://orcid.org/0000-0002-9702-8581)
- Christian Schütz (ORCID: https://orcid.org/0000-0002-2455-3123)
- Jörg Haupenthal (ORCID: https://orcid.org/0000-0003-3991-2800)
- Rolf Müller (ORCID: https://orcid.org/0000-0002-1042-5665)
- Alexander Kiefer (ORCID: https://orcid.org/0000-0002-4540-6501)
- Gabriela Krasteva‐Christ (ORCID: https://orcid.org/0000-0002-0113-521X)
- Anna K. H. Hirsch (ORCID: https://orcid.org/0000-0001-8734-4663)
- Jesko Koehnke (ORCID: https://orcid.org/0000-0002-7153-1365)
- Roya Shafiei (ORCID: https://orcid.org/0000-0001-9783-595X)
- Samira Speicher
- Niklas Wirschem
- Yu‐Mi Park
Institutions
- German Center for Infection Research (DE)
- Helmholtz Centre for Infection Research (DE)
- Helmholtz Institute for Pharmaceutical Research Saarland (DE)
- Saarland University (DE)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-02-19
- DOI
- https://doi.org/10.1002/advs.202411807
- Citations
- 6
- Primary Topic
- Antibiotic Resistance in Bacteria
- Type
- article
- Field-Weighted Citation Impact
- 3.55
Funders
- U.S. Department of Health and Human Services
- Deutsches Zentrum für Infektionsforschung
- Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator
- Deutsche Forschungsgemeinschaft
- European Synchrotron Radiation Facility
- Bundesministerium für Bildung und Forschung
- Universität des Saarlandes
- Biomedical Advanced Research and Development Authority
- Deutsches Elektronen-Synchrotron