title: Structure-guided development of efficacious antifungal agents targeting Candida glabrata dihydrofolate reductase.
abstract: Candida glabrata is a lethal fungal pathogen resistant to many antifungal agents and has emerged as a critical target for drug discovery. Over the past several years, we have been developing a class of propargyl-linked antifolates as antimicrobials and hypothesized that these compounds could be effective inhibitors of dihydrofolate reductase (DHFR) from C. glabrata. We initially screened a small collection of these inhibitors and found modest levels of potency. Subsequently, we determined the crystal structure of C. glabrata DHFR bound to a representative inhibitor with data to 1.6 A resolution. Using this structure, we designed and synthesized second-generation inhibitors. These inhibitors bind the C. glabrata DHFR enzyme with subnanomolar potency, display greater than 2000-fold levels of selectivity over the human enzyme, and inhibit the growth of C. glabrata at levels observed with clinically employed therapeutics.
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Road, Storrs, CT 0626, USA.
authors.forename: Jieying
authors.initials: J
authors.lastname: Liu
authors.forename: David B
authors.initials: DB
authors.lastname: Bolstad
authors.forename: Adrienne E
authors.initials: AE
authors.lastname: Smith
authors.forename: Nigel D
authors.initials: ND
authors.lastname: Priestley
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Wright
authors.forename: Amy C
authors.initials: AC
authors.lastname: Anderson
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology*; D041221:Candida glabrata / Q000187:drug effects* / Q000201:enzymology*; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D005493:Folic Acid Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011485:Protein Binding; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D005493:Folic Acid Antagonists; D008024:Ligands; D013762:Tetrahydrofolate Dehydrogenase