8-Mercaptoguanine Derivatives as Inhibitors of Dihydropteroate Synthase

Matthew L Dennis, Michael D Lee, Jitendra R Harjani, Mohamed Ahmed, Aaron J Debono, Noel P Pitcher, Zhong-Chang Wang, Sandeep Chhabra, Nicholas Barlow, Raphael Rahmani, Ben Cleary, Olan Dolezal, Meghan Hattarki, Luigi Aurelio, Jeremy Shonberg, Bim Graham, Thomas S Peat, Jonathan B Baell, James D Swarbrick

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

Abstract

Dihydropteroate synthase (DHPS) is an enzyme of the folate biosynthesis pathway, which catalyzes the formation of 7,8-dihydropteroate (DHPt) from 6-hydroxymethyl-7,8-dihydropterin pyrophosphate (DHPPP) and para-aminobenzoic acid (pABA). DHPS is the long-standing target of the sulfonamide class of antibiotics that compete with pABA. In the wake of sulfa drug resistance, targeting the structurally rigid (and more conserved) pterin site has been proposed as an alternate strategy to inhibit DHPS in wild-type and sulfa drug resistant strains. Following the work on developing pterin-site inhibitors of the adjacent enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), we now present derivatives of 8-mercaptoguanine, a fragment that binds weakly within both enzymes, and quantify sub-μm binding using surface plasmon resonance (SPR) to Escherichia coli DHPS (EcDHPS). Eleven ligand-bound EcDHPS crystal structures delineate the structure–activity relationship observed providing a structural framework for the rational development of novel, substrate-envelope-compliant DHPS inhibitors.

Original languageEnglish
Pages (from-to)1922-1930
Number of pages9
JournalChemistry - A European Journal
Volume24
Issue number8
DOIs
Publication statusPublished - 6 Feb 2018

Keywords

  • antibiotics
  • DHPS
  • drug discovery
  • inhibitors
  • pterin
  • substrate-envelope hypothesis

Cite this

Dennis, M. L., Lee, M. D., Harjani, J. R., Ahmed, M., Debono, A. J., Pitcher, N. P., ... Swarbrick, J. D. (2018). 8-Mercaptoguanine Derivatives as Inhibitors of Dihydropteroate Synthase. Chemistry - A European Journal, 24(8), 1922-1930. https://doi.org/10.1002/chem.201704730