title: Crystal structure of the anthrax drug target, Bacillus anthracis dihydrofolate reductase.
abstract: Spores of Bacillus anthracis are the infectious agent of anthrax. Current antibiotic treatments are limited due to resistance and patient age restrictions; thus, additional targets for therapeutic intervention are needed. One possible candidate is dihydrofolate reductase (DHFR), a biosynthetic enzyme necessary for anthrax pathogenicity. We determined the crystal structure of DHFR from B. anthracis (baDHFR) in complex with methotrexate (MTX; 1) at 2.4 Angstrom resolution. The structure reveals the crucial interactions required for MTX binding and a putative molecular basis for how baDHFR has natural resistance to trimethoprim (TMP; 2). The structure also allows insights for designing selective baDHFR inhibitors that will have weak affinities for the human enzyme. Additionally, we have found that 5-nitro-6-methylamino-isocytosine (MANIC; 3), which inhibits another B. anthracis folate synthesis enzyme, dihydropteroate synthase (DHPS), can also inhibit baDHFR. This provides a starting point for designing multi-target inhibitors that are less likely to induce drug resistance.
authors: Department of Biochemistry, Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996, USA.
authors: Brad C
authors: BC
authors: Bennett
authors: Hai
authors: H
authors: Xu
authors: Richard F
authors: RF
authors: Simmerman
authors: Richard E
authors: RE
authors: Lee
authors: Chris G
authors: CG
authors: Dealwis
mesh_terms: D000595:Amino Acid Sequence; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry; D001408:Bacillus anthracis / Q000201:enzymology*; D001426:Bacterial Proteins / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003596:Cytosine / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D008727:Methotrexate / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D016415:Sequence Alignment; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry*; D014296:Trimethoprim Resistance
chemical_list: C523907:5-nitro-6-methylaminoisocytosine; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D003596:Cytosine; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate