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Antimicrobial Agents and Chemotherapy, July 2009, p. 3065-3073, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.01666-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Crystal Structure of Bacillus anthracis Dihydrofolate Reductase with the Dihydrophthalazine-Based Trimethoprim Derivative RAB1 Provides a Structural Explanation of Potency and Selectivity{triangledown} ,{dagger}

Christina R. Bourne,1* Richard A. Bunce,2 Philip C. Bourne,1 K. Darrell Berlin,2 Esther W. Barrow,1 and William W. Barrow1*

Department of Veterinary Pathobiology, 250 McElroy Hall,1 Department of Chemistry, Physical Sciences I, Oklahoma State University, Stillwater, Oklahoma 740782

Received 18 December 2008/ Returned for modification 3 February 2009/ Accepted 6 April 2009

Bacillus anthracis possesses an innate resistance to the antibiotic trimethoprim due to poor binding to dihydrofolate reductase (DHFR); currently, there are no commercial antibacterials that target this enzyme in B. anthracis. We have previously reported a series of dihydrophthalazine-based trimethoprim derivatives that are inhibitors for this target. In the present work, we have synthesized one compound (RAB1) displaying favorable 50% inhibitory concentration (54 nM) and MIC (≤12.8 µg/ml) values. RAB1 was cocrystallized with the B. anthracis DHFR in the space group P212121, and X-ray diffraction data were collected to a 2.3-Å resolution. Binding of RAB1 causes a conformational change of the side chain of Arg58 and Met37 to accommodate the dihydrophthalazine moiety. Unlike the natural substrate or trimethoprim, the dihydrophthalazine group provides a large hydrophobic anchor that embeds within the DHFR active site and accounts for its selective inhibitory activity against B. anthracis.

* Corresponding authors. Mailing address for C. R. Bourne: Department of Veterinary Pathobiology, 250 McElroy Hall, Oklahoma State University, Stillwater, OK 74078. Phone: (405) 744-5275. Fax: (405) 744-6736. E-mail: christina.bourne{at}okstate.edu. Mailing address for W. W. Barrow: Department of Veterinary Pathobiology, 250 McElroy Hall, Oklahoma State University, Stillwater, OK 74078. Phone: (405) 744-1842. Fax: (405) 744-3738. E-mail: bill.barrow{at}okstate.edu

{triangledown} Published ahead of print on 13 April 2009.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, July 2009, p. 3065-3073, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.01666-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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