Structural basis of Pseudomonas aeruginosa penicillin binding protein 3 inhibition by the siderophore-antibiotic cefiderocol.

Autor: Smith HG; Department of Chemistry, University of Oxford 12 Mansfield Road Oxford OX1 3TA UK christopher.schofield@chem.ox.ac.uk.; Ineos Oxford Institute for Antimicrobial Research, University of Oxford 12 Mansfield Road Oxford OX1 3TA UK., Basak S; Department of Chemistry, University of Oxford 12 Mansfield Road Oxford OX1 3TA UK christopher.schofield@chem.ox.ac.uk.; Ineos Oxford Institute for Antimicrobial Research, University of Oxford 12 Mansfield Road Oxford OX1 3TA UK., Aniebok V; Department of Chemistry, University of Oxford 12 Mansfield Road Oxford OX1 3TA UK christopher.schofield@chem.ox.ac.uk.; Ineos Oxford Institute for Antimicrobial Research, University of Oxford 12 Mansfield Road Oxford OX1 3TA UK., Beech MJ; Department of Chemistry, University of Oxford 12 Mansfield Road Oxford OX1 3TA UK christopher.schofield@chem.ox.ac.uk.; Ineos Oxford Institute for Antimicrobial Research, University of Oxford 12 Mansfield Road Oxford OX1 3TA UK., Alshref FM; Department of Chemistry, University of Oxford 12 Mansfield Road Oxford OX1 3TA UK christopher.schofield@chem.ox.ac.uk.; Department of Biochemistry, Faculty of Science, King AbdulAziz University Jeddah Saudi Arabia., Allen MD; Department of Chemistry, University of Oxford 12 Mansfield Road Oxford OX1 3TA UK christopher.schofield@chem.ox.ac.uk.; Ineos Oxford Institute for Antimicrobial Research, University of Oxford 12 Mansfield Road Oxford OX1 3TA UK., Farley AJM; Department of Chemistry, University of Oxford 12 Mansfield Road Oxford OX1 3TA UK christopher.schofield@chem.ox.ac.uk.; Ineos Oxford Institute for Antimicrobial Research, University of Oxford 12 Mansfield Road Oxford OX1 3TA UK., Schofield CJ; Department of Chemistry, University of Oxford 12 Mansfield Road Oxford OX1 3TA UK christopher.schofield@chem.ox.ac.uk.; Ineos Oxford Institute for Antimicrobial Research, University of Oxford 12 Mansfield Road Oxford OX1 3TA UK.
Jazyk: angličtina
Zdroj: Chemical science [Chem Sci] 2024 Sep 18. Date of Electronic Publication: 2024 Sep 18.
DOI: 10.1039/d4sc04937c
Abstrakt: 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 via 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 Pseudomonas aeruginosa PBP3, including inhibition measurements, protein observed mass spectrometry, and X-ray crystallography. The three cephalosporins form analogous 3-exomethylene products with P. aeruginosa PBP3 following elimination of the C3' side chain. pIC 50 and k inact / K i measurements with isolated PBP3 imply ceftazidime and cefiderocol react less efficiently than cefepime and, in particular, meropenem with P. aeruginosa PBP3. Crystal structures inform on conserved and different interactions involved in binding of the three cephalosporins and meropenem to P. aeruginosa PBP3. The results will aid development of cephalosporins with improved PBP3 inhibition properties.
Competing Interests: The authors have no conflicts to declare.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
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