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Rational inhibitor design for Pseudomonas aeruginosa salicylate adenylation enzyme PchD

Shelton, Catherine L.
Meneely, Kathleen M.
Ronnebaum, Trey A.
Chilton, Annemarie S.
Riley, Andrew P.
Prisinzano, Thomas E.
Lamb, Audrey L.
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Abstract
Pseudomonas aeruginosa is an increasingly antibiotic-resistant pathogen that causes severe lung infections, burn wound infections, and diabetic foot infections. P. aeruginosa produces the siderophore pyochelin through the use of a non-ribosomal peptide synthetase (NRPS) biosynthetic pathway. Targeting members of siderophore NRPS proteins is one avenue currently under investigation for the development of new antibiotics against antibiotic-resistant organisms. Here, the crystal structure of the pyochelin adenylation domain PchD is reported. The structure was solved to 2.11 Å when co-crystallized with the adenylation inhibitor 5′-O-(N-salicylsulfamoyl)adenosine (salicyl-AMS) and to 1.69 Å with a modified version of salicyl-AMS designed to target an active site cysteine (4-cyano-salicyl-AMS). In the structures, PchD adopts the adenylation conformation, similar to that reported for AB3403 from Acinetobacter baumannii.
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Date
2022-05-05
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Publisher
Springer
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Keywords
Adenylation domain, Pseudomonas aeruginosa, Inhibitor design, Antibiotic resistance, Pyochelin
Citation
Shelton, C.L., Meneely, K.M., Ronnebaum, T.A. et al. Rational inhibitor design for Pseudomonas aeruginosa salicylate adenylation enzyme PchD. J Biol Inorg Chem 27, 541–551 (2022). https://doi.org/10.1007/s00775-022-01941-8
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