Synthetic and crystallographic studies of a new inhibitor series targeting Bacillus anthracis dihydrofolate reductase

Jennifer M Beierlein; Kathleen M Frey; David B Bolstad; Phillip M Pelphrey; Tammy M Joska; Adrienne E Smith; Nigel D Priestley; Dennis L Wright; Amy C Anderson

doi:10.1021/jm800776a

Synthetic and crystallographic studies of a new inhibitor series targeting Bacillus anthracis dihydrofolate reductase

J Med Chem. 2008 Dec 11;51(23):7532-40. doi: 10.1021/jm800776a.

Authors

Jennifer M Beierlein¹, Kathleen M Frey, David B Bolstad, Phillip M Pelphrey, Tammy M Joska, Adrienne E Smith, Nigel D Priestley, Dennis L Wright, Amy C Anderson

Affiliation

¹ Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Road, Storrs, Connecticut 06269, USA.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Amino Acid Sequence
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology
Bacillus anthracis / drug effects
Bacillus anthracis / enzymology*
Binding Sites / drug effects
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Design
Enzyme Inhibitors* / chemical synthesis
Enzyme Inhibitors* / chemistry
Enzyme Inhibitors* / pharmacology
Humans
Ligands
Microbial Sensitivity Tests
Models, Molecular
Molecular Sequence Data
Molecular Structure
Molecular Weight
Recombinant Proteins / biosynthesis
Recombinant Proteins / drug effects
Recombinant Proteins / isolation & purification
Sequence Alignment
Stereoisomerism
Structure-Activity Relationship
Tetrahydrofolate Dehydrogenase / biosynthesis
Tetrahydrofolate Dehydrogenase / drug effects*
Tetrahydrofolate Dehydrogenase / isolation & purification

Substances

Anti-Bacterial Agents
Enzyme Inhibitors
Ligands
Recombinant Proteins
Tetrahydrofolate Dehydrogenase

Abstract

Publication types

MeSH terms

Substances

Grants and funding