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

Author:

Bourne Christina R.1,Bunce Richard A.2,Bourne Philip C.1,Berlin K. Darrell2,Barrow Esther W.1,Barrow William W.1

Affiliation:

1. Department of Veterinary Pathobiology, 250 McElroy Hall

2. Department of Chemistry, Physical Sciences I, Oklahoma State University, Stillwater, Oklahoma 74078

Abstract

ABSTRACT 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 P2 1 2 1 2 1 , 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 .

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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