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 journalArticle

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.

LanguageEnglish
Pages1922-1930
Number of pages9
JournalChemistry-A European Journal
Volume24
Issue number8
DOIs
StatePublished - 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. DOI: 10.1002/chem.201704730
Dennis, Matthew L ; Lee, Michael D ; Harjani, Jitendra R ; Ahmed, Mohamed ; Debono, Aaron J ; Pitcher, Noel P ; Wang, Zhong-Chang ; Chhabra, Sandeep ; Barlow, Nicholas ; Rahmani, Raphael ; Cleary, Ben ; Dolezal, Olan ; Hattarki, Meghan ; Aurelio, Luigi ; Shonberg, Jeremy ; Graham, Bim ; Peat, Thomas S ; Baell, Jonathan B ; Swarbrick, James D. / 8-Mercaptoguanine Derivatives as Inhibitors of Dihydropteroate Synthase. In: Chemistry-A European Journal. 2018 ; Vol. 24, No. 8. pp. 1922-1930
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Dennis, ML, Lee, MD, Harjani, JR, Ahmed, M, Debono, AJ, Pitcher, NP, Wang, Z-C, Chhabra, S, Barlow, N, Rahmani, R, Cleary, B, Dolezal, O, Hattarki, M, Aurelio, L, Shonberg, J, Graham, B, Peat, TS, Baell, JB & Swarbrick, JD 2018, '8-Mercaptoguanine Derivatives as Inhibitors of Dihydropteroate Synthase' Chemistry-A European Journal, vol 24, no. 8, pp. 1922-1930. DOI: 10.1002/chem.201704730

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

In: Chemistry-A European Journal, Vol. 24, No. 8, 06.02.2018, p. 1922-1930.

Research output: Contribution to journalArticle

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AU - Hattarki,Meghan

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Dennis ML, Lee MD, Harjani JR, Ahmed M, Debono AJ, Pitcher NP et al. 8-Mercaptoguanine Derivatives as Inhibitors of Dihydropteroate Synthase. Chemistry-A European Journal. 2018 Feb 6;24(8):1922-1930. Available from, DOI: 10.1002/chem.201704730