Download MendeleyDipeptidic Phosphonates: Potent Inhibitors of Pseudomonas aeruginosa Elastase B Showing Efficacy in a Murine Keratitis Model.
Kiefer, A.F., Schutz, C., Englisch, C.N., Kolling, D., Speicher, S., Kany, A.M., Shafiei, R., Wadood, N.A., Aljohmani, A., Wirschem, N., Jumde, R.P., Klein, A., Sikandar, A., Park, Y.M., Krasteva-Christ, G., Yildiz, D., Abdelsamie, A.S., Rox, K., Kohnke, J., Muller, R., Bischoff, M., Haupenthal, J., Hirsch, A.K.H.(2025) Adv Sci (Weinh) 12: e2411807-e2411807
- PubMed: 39973061
- DOI: https://doi.org/10.1002/advs.202411807
- Primary Citation of Related Structures:
8R1B, 9FQD, 9FQY - PubMed 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.
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus E8.1, 66123, Saarbrücken, Germany.
Organizational Affiliation:
