Register      Login
Australian Journal of Chemistry Australian Journal of Chemistry Society
An international journal for chemical science
Shopping Cart: ( empty )
You are here: Home > Journals > CH > CH13298
RESEARCH FRONT
Contents Vol 66(12)

Fragment Screening on Staphylococcus aureus HPPK – a Folate Pathway Target

Sandeep Chhabra A , Olan Dolezal B , Meghan Hattarki B , Thomas S. Peat B , Jamie S. Simpson A and James D. Swarbrick A C
+ Author Affiliations
- Author Affiliations

A Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University,399 Royal Parade, Parkville, Vic. 3052, Australia.

B CSIRO Division of Materials, Science and Engineering, 343 Royal Parade, Parkville, Vic. 3052, Australia.

C Corresponding author. Email: james.swarbrick@monash.edu

Australian Journal of Chemistry 66(12) 1537-1543 https://doi.org/10.1071/CH13298
Submitted: 10 June 2013  Accepted: 12 August 2013   Published: 20 September 2013

Abstract

An NMR-based screen of a commercially available fragment library was performed on the folate pathway antimicrobial target, 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase from Staphylococcus aureus (SaHPPK). Initial 1D saturation transfer difference-NMR screening resulted in an impractically high hit rate (43 %), which advocated the use of a strategy based on 2D (SOFAST) 15N HMQC NMR experiments. Chemical shift perturbations were used to identify, validate, and map the location of 16 initial binders (hit rate of 2 %). Fourteen compounds were purchased based on an identified thioamide pharmacophore. Binding affinities (Kd) were measured by surface plasmon resonance, revealing a modest improvement in potency over the initial 16 hits, with the best fragment found to bind to the apo enzyme with a Kd of 420 µM, corresponding to a ligand efficiency of 1.8 kJ/heavy atom. Four fragments identified represent useful starting points for the generation of leads that may ultimately be developed into new antimicrobial agents.


References

[1]  A. Bermingham, J. P. Derrick, BioEssays 2002, 24, 637.
         | 1:CAS:528:DC%2BD38XlvVSntr8%3D&md5=c62b99b6fbe5ce285bd101b90b8e7fd0CAS | 12111724PubMed |

[2]  J. D. Swarbrick, P. Iliades, J. S. Simpson, I. Macreadie, Open Enzyme Inhibition J. 2008, 1, 12.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXps1ajsLs%3D&md5=af94337e8847cd38616d21a51aaea19cCAS |

[3]  P. C. Appelbaum, Clinical Microbiol Infect 2006, 12, 3.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XltlGnsbg%3D&md5=996277c06fb6db0bbb7f784cbeaf666dCAS |

[4]  R. H. Drew, Pharmacotherapy 2007, 27, 227.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXitlyjsb8%3D&md5=9f7a869891b452e75a5496ddbb84d564CAS | 17253914PubMed |

[5]  M. F. Kluytmans-VandenBergh, J. A. Kluytmans, Clinical Microbiol Infect 2006, 12, 9.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XjsFOrurw%3D&md5=65cbf191c7e56a874dae3ecd5f54d129CAS |

[6]  M. H. Kollef, S. T. Micek, Curr. Opin. Infect. Dis. 2006, 19, 161.
         | 16514341PubMed |

[7]  M. Li, B. A. Diep, A. E. Villaruz, K. R. Braughton, X. Jiang, F. R. DeLeo, H. F. Chambers, Y. Lu, M. Otto, Proc. Natl. Acad. Sci. USA 2009, 106, 5883.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXkvFeisrY%3D&md5=b880fe6aedb5d71968df0d7bbaf4e0c7CAS | 19293374PubMed |

[8]  C. R. Bourne, R. A. Bunce, P. C. Bourne, K. D. Berlin, E. W. Barrow, W. W. Barrow, Antimicrob. Agents Chemother. 2009, 53, 3065.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXotlajs7s%3D&md5=8dbbffecde1e0d0b33692a92b101c702CAS | 19364848PubMed |

[9]  M. K. Yun, Y. Wu, Z. Li, Y. Zhao, M. B. Waddell, A. M. Ferreira, R. E. Lee, D. Bashford, S. W. White, Science 2012, 335, 1110.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XivVGhtrg%3D&md5=5230aceb789af27fecc0cb21c1b353f2CAS | 22383850PubMed |

[10]  H. Haruki, M. G. Pedersen, K. I. Gorska, F. Pojer, K. Johnsson, Science 2013, 340, 987.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXnvFSrtb4%3D&md5=76b3f9f70df195c32541bcd331f4fc05CAS | 23704574PubMed |

[11]  R. R. Chaudhuri, A. G. Allen, P. J. Owen, G. Shalom, K. Stone, M. Harrison, T. A. Burgis, M. Lockyer, J. Garcia-Lara, S. J. Foster, S. J. Pleasance, S. E. Peters, D. J. Maskell, I. G. Charles, BMC Genomics 2009, 10, 291.
         | Crossref | GoogleScholarGoogle Scholar | 19570206PubMed |

[12]  M. Jönsson, G. Swedberg, Mol. Biochem. Parasitol. 2005, 140, 123.
         | Crossref | GoogleScholarGoogle Scholar | 15694494PubMed |

[13]  W. Rattanachuen, M. Jonsson, G. Swedberg, W. Sirawaraporn, Mol. Biochem. Parasitol. 2009, 168, 135.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXhtFyqtbbP&md5=cadf1ce06d003b7f7353027a988f1db7CAS | 19631695PubMed |

[14]  S. Chhabra, O. Dolezal, B. M. Collins, J. Newman, J. S. Simpson, I. G. Macreadie, R. Fernley, T. S. Peat, J. D. Swarbrick, PLoS ONE 2012, 7, e29444.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XhvVyks7c%3D&md5=829142e0dc9988934ee711eb10c8e674CAS | 22276115PubMed |

[15]  S. Chhabra, N. Barlow, O. Dolezal, M. K. Hattarki, J. Newman, T. S. Peat, B. Graham, J. D. Swarbrick, PLoS ONE 2013, 8, e59535.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXmtVeitLk%3D&md5=2958400f0512e2b4c3d047c8a5ea3001CAS | 23565155PubMed |

[16]  G. Shi, J. Blaszczyk, X. Ji, H. Yan, J. Med. Chem. 2001, 44, 1364.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXitFGmtLs%3D&md5=a3677023d815c53c0584363ae33ddba2CAS | 11311059PubMed |

[17]  G. Shi, G. Shaw, Y. H. Liang, P. Subburaman, Y. Li, Y. Wu, H. Yan, X. Ji, Bioorg. Med. Chem. 2012, 20, 47.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XitlGltg%3D%3D&md5=3b77f33429e7165bcdc10040d7531df2CAS | 22169600PubMed |

[18]  D. K. Stammers, A. Achari, D. O. Somers, P. K. Bryant, J. Rosemond, D. L. Scott, J. N. Champness, FEBS Lett. 1999, 456, 49.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXlsFSlu7w%3D&md5=5115330aeabe1843f70dfd98292ce8cfCAS | 10452528PubMed |

[19]  H. C. S. Wood, Specific inhibition of dihydrofolate biosynthesis–a new approach to chemotherapy, in Chemistry and Biology of Pteridines (Ed W. Pfleiderer) 1975 (Walter de Gruyter: Berlin).

[20]  R. Campos-Olivas, Curr. Top. Med. Chem. 2011, 11, 43.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXkslaiurw%3D&md5=ce17fea648c6717375a3b54f0b4a06daCAS | 20809889PubMed |

[21]  C. A. Lepre, Methods Enzymol. 2011, 493, 219.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXoslersrw%3D&md5=3cda5e6f250768ca97a7eee945236befCAS | 21371593PubMed |

[22]  P. Schanda, E. Kupce, B. Brutscher, J. Biomol. NMR 2005, 33, 199.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXhtlSjtLbF&md5=f02f3d3ef627b762448dc04971840fa8CAS | 16341750PubMed |

[23]  P. J. Hajduk, J. Med. Chem. 2006, 49, 6972.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XhtFOmtLbJ&md5=b4b15be1673dabeca2e6942577e6492eCAS | 17125250PubMed |

[24]  A. L. Hopkins, C. R. Groom, A. Alex, Drug Discov. Today 2004, 9, 430.
         | Crossref | GoogleScholarGoogle Scholar | 15109945PubMed |

[25]  F. Wang, R. Langley, G. Gulten, L. G. Dover, G. S. Besra, W. R. Jacobs, J. C. Sacchettini, J. Exp. Med. 2007, 204, 73.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXhtFGjtr8%3D&md5=f3a0878ee65422daeb2be5d79aa8ade7CAS | 17227913PubMed |

[26]  M. Buchholz, U. Heiser, S. Schilling, A. J. Niestroj, K. Zunkel, H. U. Demuth, J. Med. Chem. 2006, 49, 664.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XotlWrug%3D%3D&md5=00dc43cf854de81e2a0a535a3f885300CAS | 16420052PubMed |

[27]  M. N. Schulz, J. Landstrom, K. Bright, R. E. Hubbard, J. Comput. Aided Mol. Des. 2011, 25, 611.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXhtVSqtbfJ&md5=008990a5942a2baf3a4e00e311ed13b2CAS | 21792630PubMed |

[28]  B. J. Davis, D. A. Erlanson, Bioorg. Med. Chem. Lett. 2013, 23, 2844.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXltlOns7s%3D&md5=3c69458b6ebf979de109ae610fcd898dCAS | 23562240PubMed |

[29]  M. Piotto, V. Saudek, V. Sklenar, J. Biomol. NMR 1992, 2, 661.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK3sXitVyktrY%3D&md5=860b5da0048853ea4c357a905e62dafcCAS | 1490109PubMed |

[30]  F. Delaglio, S. Grzesiek, G. W. Vuister, G. Zhu, J. Pfeifer, A. Bax, J. Biomol. NMR 1995, 6, 277.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2MXhtVSmurfK&md5=98e99a6ef19189a5c6b80a78f914d0f6CAS | 8520220PubMed |

[31]  T. D. Goddard, D. G. Kneller, Sparky Version 3.113 20xx (University of California: San Francisco). www.cgl.ucsf.edu/home/sparky (verified August 2013)