Crystal structure of the anthrax drug target, Bacillus anthracis dihydrofolate reductase.
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.
Bennett
Brad C
BC
Department of Biochemistry, Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996, USA.
Xu
Hai
H
Simmerman
Richard F
RF
Lee
Richard E
RE
Dealwis
Chris G
CG
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
C523907:5-nitro-6-methylaminoisocytosine; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D003596:Cytosine; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate