TY - JOUR
T1 - Rational inhibitor design for Pseudomonas aeruginosa salicylate adenylation enzyme PchD
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.
N1 - Publisher Copyright:
© 2022, The Author(s).
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
UR - http://www.scopus.com/inward/record.url?scp=85129446041&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85129446041&partnerID=8YFLogxK
U2 - 10.1007/s00775-022-01941-8
DO - 10.1007/s00775-022-01941-8
M3 - Article
C2 - 35513576
AN - SCOPUS:85129446041
SN - 0949-8257
VL - 27
SP - 541
EP - 551
JO - Journal of Biological Inorganic Chemistry
JF - Journal of Biological Inorganic Chemistry
IS - 6
ER -
