1. Rational inhibitor design for Pseudomonas aeruginosa salicylate adenylation enzyme PchD.
- Author
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Shelton CL, Meneely KM, Ronnebaum TA, Chilton AS, Riley AP, Prisinzano TE, and Lamb AL
- Subjects
- Anti-Bacterial Agents metabolism, Anti-Bacterial Agents pharmacology, Phenols, Salicylates metabolism, Thiazoles, Pseudomonas aeruginosa metabolism, Siderophores chemistry
- 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., (© 2022. The Author(s).)
- Published
- 2022
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