Rational inhibitor design for Pseudomonas aeruginosa salicylate adenylation enzyme PchD

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

Research output: Contribution to journalArticlepeer-review

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. Graphical abstract: [Figure not available: see fulltext.]

Original languageEnglish
Pages (from-to)541-551
Number of pages11
JournalJournal of Biological Inorganic Chemistry
Volume27
Issue number6
DOIs
StatePublished - Sep 2022

Bibliographical note

Funding Information:
Diffraction data were collected at the Stanford Synchrotron Radiation Laboratory. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE0AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institute of Health, National Institute of General Medical Sciences (P41GM103393). CLS was supported at the University of Kansas by an IRACDA fellowship from the National Institute of General Medical Science (NIGMS) NIH Grant #K12GM063651 and is currently supported by an IDeA grant through the Kentucky IDeA Networks of Biomedical Research Excellence (KY INBRE) NIGMS #5P20GM103436. TAR and APR were supported at the University of Kansas by the National Institutes of Health Graduate Training Program in the Dynamic Aspects of Chemical Biology #T32GM008545 and is currently supported by the Ruth L. Kirschstein NRSA F32 Postdoctoral Fellowship #GM137461. TEP was supported by the National Institutes of Health #P20GM113117. ALL was supported by the National Institutes of Health #R01GM127655 and the National Science Foundation #1904494 and #2041047.

Funding Information:
Diffraction data were collected at the Stanford Synchrotron Radiation Laboratory. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE0AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institute of Health, National Institute of General Medical Sciences (P41GM103393). CLS was supported at the University of Kansas by an IRACDA fellowship from the National Institute of General Medical Science (NIGMS) NIH Grant #K12GM063651 and is currently supported by an IDeA grant through the Kentucky IDeA Networks of Biomedical Research Excellence (KY INBRE) NIGMS #5P20GM103436. TAR and APR were supported at the University of Kansas by the National Institutes of Health Graduate Training Program in the Dynamic Aspects of Chemical Biology #T32GM008545 and is currently supported by the Ruth L. Kirschstein NRSA F32 Postdoctoral Fellowship #GM137461. TEP was supported by the National Institutes of Health #P20GM113117. ALL was supported by the National Institutes of Health #R01GM127655 and the National Science Foundation #1904494 and #2041047.

Publisher Copyright:
© 2022, The Author(s).

Keywords

  • Adenylation domain
  • Antibiotic resistance
  • Inhibitor design
  • Pseudomonas aeruginosa
  • Pyochelin

ASJC Scopus subject areas

  • Biochemistry
  • Inorganic Chemistry

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