Structure-Guided Development of Efficacious Antifungal Agents Targeting Candida glabrata Dihydrofolate Reductase

Jieying Liu, David B. Bolstad, Adrienne E. Smith, Nigel D. Priestley, Dennis L. Wright, Amy C. Anderson

Research output: Contribution to journalArticlepeer-review

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 Å 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.

Original languageEnglish
Pages (from-to)990-996
Number of pages7
JournalChemistry and Biology
Volume15
Issue number9
DOIs
StatePublished - Sep 22 2008

Keywords

  • CHEMBIO

Fingerprint

Dive into the research topics of 'Structure-Guided Development of Efficacious Antifungal Agents Targeting Candida glabrata Dihydrofolate Reductase'. Together they form a unique fingerprint.

Cite this