9FZ8

Pseudomonas aeruginosa penicillin binding protein 3

Summary for 9FZ8

• Entry DOI: 10.2210/pdb9fz8/pdb
• Descriptor: Peptidoglycan D,D-transpeptidase FtsI (2 entities in total)
• Functional Keywords: transpeptidase, penicillin binding protein, pbp3, hydrolase
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 1
• Total formula weight: 56007.83

Authors

Smith, H.G.,Allen, M.D.,Basak, S.,Aniebok, V.,Beech, M.J.,Alshref, F.M.,Farley, A.J.M.,Schofield, C.J. (deposition date: 2024-07-04, release date: 2024-10-09, Last modification date: 2024-11-06)

Primary citation

Smith, H.G.,Basak, S.,Aniebok, V.,Beech, M.J.,Alshref, F.M.,Allen, M.D.,Farley, A.J.M.,Schofield, C.J.
Structural basis of Pseudomonas aeruginosa penicillin binding protein 3 inhibition by the siderophore-antibiotic cefiderocol.
Chem Sci, 15:16928-16937, 2024

PubMed Abstract: The breakthrough cephalosporin cefiderocol, approved for clinical use in 2019, has activity against many Gram-negative bacteria. The catechol group of cefiderocol enables it to efficiently enter bacterial cells the iron/siderophore transport system thereby reducing resistance due to porin channel mutations and efflux pump upregulation. Limited information is reported regarding the binding of cefiderocol to its key proposed target, the transpeptidase penicillin binding protein 3 (PBP3). We report studies on the reaction of cefiderocol and the related cephalosporins ceftazidime and cefepime with PBP3, including inhibition measurements, protein observed mass spectrometry, and X-ray crystallography. The three cephalosporins form analogous 3-exomethylene products with PBP3 following elimination of the C3' side chain. pIC and / measurements with isolated PBP3 imply ceftazidime and cefiderocol react less efficiently than cefepime and, in particular, meropenem with PBP3. Crystal structures inform on conserved and different interactions involved in binding of the three cephalosporins and meropenem to PBP3. The results will aid development of cephalosporins with improved PBP3 inhibition properties.

PubMed: 39328188
DOI: 10.1039/d4sc04937c

Experimental method

X-RAY DIFFRACTION (2.11 Å)