Rational inhibitor design for Pseudomonas aeruginosa salicylate adenylation enzyme PchD.

Autor: Shelton CL; Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66045, USA.; Department of Chemistry and Biochemistry, Northern Kentucky University, Highland Heights, Kentucky, 41099, USA., Meneely KM; Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66045, USA.; Department of Chemistry, University of Texas San Antonio, San Antonio, TX, 78249, USA., Ronnebaum TA; Department of Chemistry, University of Kansas, Lawrence, KS, 66045, USA.; Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA, 19104-6323, USA., Chilton AS; Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66045, USA., Riley AP; Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60612, USA.; Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS, 66045, USA., Prisinzano TE; Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS, 66045, USA.; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, 40536-0596, USA., Lamb AL; Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66045, USA. audrey.lamb@utsa.edu.; Department of Chemistry, University of Texas San Antonio, San Antonio, TX, 78249, USA. audrey.lamb@utsa.edu.
Jazyk: angličtina
Zdroj: Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry [J Biol Inorg Chem] 2022 Sep; Vol. 27 (6), pp. 541-551. Date of Electronic Publication: 2022 May 05.
DOI: 10.1007/s00775-022-01941-8
Abstrakt: 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).)
Databáze: MEDLINE
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