Journal Article

Rational inhibitor design for Pseudomonas aeruginosa salicylate adenylation enzyme PchD

Meneely, Kathleen M, Ronnebaum, Trey A, Lamb, Audrey L, Shelton, Catherine L, Chilton, Annemarie S, Riley, Andrew P, Prisinzano, Thomas E

2022

Overview

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.Graphical abstract

• Publisher: Springer Nature B.V
• Subject: Adenosine / Adenylation / Antibiotic resistance / Antibiotics / Bacteria / Biosynthesis / Bronchopulmonary infection / Chromatography / Conformation / Crystal structure / Crystallization / Diabetes mellitus / Drug resistance / Enzymes / Glycerol / Inhibitors / Metals / Pathogens / Peptides / Proteins / Pseudomonas aeruginosa / Salicylic acid / Tuberculosis / Wound infection