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: Research - peer-reviewArticle

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-dihydropterinpyrophosphate (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 work 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
Number of pages10
JournalChemistry-A European Journal
DOIs
StateAccepted/In press - 2017

Keywords

  • DHPS
  • inhibitor
  • pterin
  • antibiotic
  • drug discovery

Cite this

Dennis, M. L., Lee, M. D., Harjani, J. R., Ahmed, M., Debono, A. J., Pitcher, N. P., ... Swarbrick, J. D. (2017). 8-Mercaptoguanine derivatives as inhibitors of dihydropteroate synthase. Chemistry-A European Journal. 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. 2017
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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-dihydropterinpyrophosphate (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 work 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.",
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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 2017, '8-Mercaptoguanine derivatives as inhibitors of dihydropteroate synthase' Chemistry-A European Journal. 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, 2017.

Research output: Research - peer-reviewArticle

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T1 - 8-Mercaptoguanine derivatives as inhibitors of dihydropteroate synthase

AU - Dennis,Matthew L

AU - Lee,Michael D

AU - Harjani,Jitendra R

AU - Ahmed,Mohamed

AU - Debono,Aaron J

AU - Pitcher,Noel P

AU - Wang,Zhong-Chang

AU - Chhabra,Sandeep

AU - Barlow,Nicholas

AU - Rahmani,Raphael

AU - Cleary,Ben

AU - Dolezal,Olan

AU - Hattarki,Meghan

AU - Aurelio,Luigi

AU - Shonberg,Jeremy

AU - Graham,Bim

AU - Peat,Thomas S

AU - Baell,Jonathan B

AU - Swarbrick,James D

PY - 2017

Y1 - 2017

N2 - 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-dihydropterinpyrophosphate (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 work 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.

AB - 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-dihydropterinpyrophosphate (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 work 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.

KW - DHPS

KW - inhibitor

KW - pterin

KW - antibiotic

KW - drug discovery

U2 - 10.1002/chem.201704730

DO - 10.1002/chem.201704730

M3 - Article

JO - Chemistry-A European Journal

T2 - Chemistry-A European Journal

JF - Chemistry-A European Journal

SN - 0947-6539

ER -

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. 2017. Available from, DOI: 10.1002/chem.201704730