title: Pterin-sulfa conjugates as dihydropteroate synthase inhibitors and antibacterial agents.
abstract: The sulfonamide class of antibiotics has been in continuous use for over 70years. They are thought to act by directly inhibiting dihydropteroate synthase (DHPS), and also acting as prodrugs that sequester pterin pools by forming dead end pterin-sulfonamide conjugates. In this study, eight pterin-sulfonamide conjugates were synthesized using a novel synthetic strategy and their biochemical and microbiological properties were investigated. The conjugates were shown to competitively inhibit DHPS, and inhibition was enhanced by the presence of pyrophosphate that is crucial to catalysis and is known to promote an ordering of the DHPS active site. The co-crystal structure of Yersinia pestis DHPS bound to one of the more potent conjugates revealed a mode of binding that is similar to that of the enzymatic product analog pteroic acid. The antimicrobial activities of the pterin-sulfonamide conjugates were measured against Escherichia coli in the presence and absence of folate precursors and dependent metabolites. These results show that the conjugates have appreciable antibacterial activity and act by an on target, anti-folate pathway mechanism rather than as simple dead end products.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 1000, Memphis, TN 38105, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 1000, Memphis, TN 38105, United States.
authors.forename: William R
authors.initials: WR
authors.lastname: Shadrick
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 1000, Memphis, TN 38105, United States.
authors.forename: Miranda J
authors.initials: MJ
authors.lastname: Wallace
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 311, Memphis, TN 38105, United States; Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 311, Memphis, TN 38105, United States.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Griffith
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Qi
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 311, Memphis, TN 38105, United States.
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Yun
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 311, Memphis, TN 38105, United States; Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: White
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 1000, Memphis, TN 38105, United States; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004094:Dihydropteroate Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects; D005492:Folic Acid / Q000737:chemistry; D062105:Molecular Docking Simulation; D011622:Pterins / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D015010:Yersinia pestis / Q000201:enzymology
chemical_list: D000900:Anti-Bacterial Agents; D011622:Pterins; D013449:Sulfonamides; D005492:Folic Acid; D004094:Dihydropteroate Synthase
keywords: Antibiotics; Antifolate; Dihydropteroate synthase; Pterin; Sulfonamide