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

doi:10.1007/s00775-022-01941-8

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 journal › Article › peer-review

8 Scopus citations

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 language	English
Pages (from-to)	541-551
Number of pages	11
Journal	Journal of Biological Inorganic Chemistry
Volume	27
Issue number	6
DOIs	https://doi.org/10.1007/s00775-022-01941-8
State	Published - Sep 2022

Bibliographical note

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

Funding

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. 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.

Funders	Funder number
Kentucky IDeA Networks of Biomedical Research Excellence	5P20GM103436
National Science Foundation Arctic Social Science Program	1904494, 2041047
National Science Foundation Arctic Social Science Program
National Institutes of Health (NIH)	12GM063651, 32GM008545
National Institutes of Health (NIH)
U.S. Department of Energy EPSCoR
National Institute of General Medical Sciences	F32GM137461, P41GM103393
National Institute of General Medical Sciences
Office of Science Programs
DOE Basic Energy Sciences	DE0AC02-76SF00515
DOE Basic Energy Sciences
Biological and Environmental Research
University of Kansas and University of Kansas Cancer Center
Israel National Road Safety Authority	20GM113117, 01GM127655, 137461
Israel National Road Safety Authority
Kentucky IDeA Networks of Biomedical Research Excellence

Keywords

Adenylation domain
Antibiotic resistance
Inhibitor design
Pseudomonas aeruginosa
Pyochelin

ASJC Scopus subject areas

Biochemistry
Inorganic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s00775-022-01941-8

Cite this

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title = "Rational inhibitor design for Pseudomonas aeruginosa salicylate adenylation enzyme PchD",

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 {\AA} when co-crystallized with the adenylation inhibitor 5′-O-(N-salicylsulfamoyl)adenosine (salicyl-AMS) and to 1.69 {\AA} 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.]",

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author = "Shelton, {Catherine L.} and Meneely, {Kathleen M.} and Ronnebaum, {Trey A.} and Chilton, {Annemarie S.} and Riley, {Andrew P.} and Prisinzano, {Thomas E.} and Lamb, {Audrey L.}",

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year = "2022",

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doi = "10.1007/s00775-022-01941-8",

language = "English",

volume = "27",

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AU - Shelton, Catherine L.

AU - Meneely, Kathleen M.

AU - Ronnebaum, Trey A.

AU - Chilton, Annemarie S.

AU - Riley, Andrew P.

AU - Prisinzano, Thomas E.

AU - Lamb, Audrey L.

PY - 2022/9

Y1 - 2022/9

N2 - 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.]

AB - 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.]

KW - Adenylation domain

KW - Antibiotic resistance

KW - Inhibitor design

KW - Pseudomonas aeruginosa

KW - Pyochelin

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Rational inhibitor design for Pseudomonas aeruginosa salicylate adenylation enzyme PchD

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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