title: Synthetic and crystallographic studies of a new inhibitor series targeting Bacillus anthracis dihydrofolate reductase.
abstract: Bacillus anthracis, the causative agent of anthrax, poses a significant biodefense danger. Serious limitations in approved therapeutics and the generation of resistance have produced a compelling need for new therapeutic agents against this organism. Bacillus anthracis is known to be insensitive to the clinically used antifolate, trimethoprim, because of a lack of potency against the dihydrofolate reductase enzyme. Herein, we describe a novel lead series of B. anthracis dihydrofolate reductase inhibitors characterized by an extended trimethoprim-like scaffold. The best lead compound adds only 22 Da to the molecular weight and is 82-fold more potent than trimethoprim. An X-ray crystal structure of this lead compound bound to B. anthracis dihydrofolate reductase in the presence of NADPH was determined to 2.25 A resolution. The structure reveals several features that can be exploited for further development of this lead series.
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Road, Storrs, Connecticut 06269, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Beierlein
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Frey
authors.forename: David B
authors.initials: DB
authors.lastname: Bolstad
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Pelphrey
authors.forename: Tammy M
authors.initials: TM
authors.lastname: Joska
authors.forename: Adrienne E
authors.initials: AE
authors.lastname: Smith
authors.forename: Nigel D
authors.initials: ND
authors.lastname: Priestley
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Wright
authors.forename: Amy C
authors.initials: AC
authors.lastname: Anderson
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001408:Bacillus anthracis / Q000187:drug effects / Q000201:enzymology*; D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D008970:Molecular Weight; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000302:isolation & purification; D016415:Sequence Alignment; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000096:biosynthesis / Q000187:drug effects* / Q000302:isolation & purification
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D011994:Recombinant Proteins; D013762:Tetrahydrofolate Dehydrogenase