8R1B

Crystal structure of recombinant LasB from Pseudomonas aeruginosa PAO1 in complex with 6466

Summary for 8R1B

• Entry DOI: 10.2210/pdb8r1b/pdb
• Descriptor: Pro-elastase, ZINC ION, CALCIUM ION, ... (7 entities in total)
• Functional Keywords: thermolysin metallopeptidase, catalytic domain in complex with a small molecule inhibitor, hydrolase
• Biological source: Pseudomonas aeruginosa PAO1
• Total number of polymer chains: 1
• Total formula weight: 56525.19

Authors

Kolling, D.,Koehnke, J. (deposition date: 2023-11-01, release date: 2024-10-16, Last modification date: 2025-04-23)

Primary citation

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.
Dipeptidic Phosphonates: Potent Inhibitors of Pseudomonas aeruginosa Elastase B Showing Efficacy in a Murine Keratitis Model.
Adv Sci, 12:e2411807-e2411807, 2025

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.

PubMed: 39973061
DOI: 10.1002/advs.202411807

Experimental method

X-RAY DIFFRACTION (1.31 Å)