Furan-based benzene mono- and dicarboxylic acid derivatives as multiple inhibitors of the bacterial Mur ligases (MurC–MurF): experimental and computational characterization

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• 作者：Andrej Perdih ; Martina Hrast ; Kaja Pureber…
• 关键词：Bacterial Mur (MurC–MurF) ligase ; ATP ; competitive inhibition ; Molecular dynamics (MD) ; Steady ; state kinetics measurements ; Antibacterial agents ; Drug design
• 刊名：Journal of Computer-Aided Molecular Design
• 出版年：2015
• 出版时间：June 2015
• 年：2015
• 卷：29
• 期：6
• 页码：541-560
• 全文大小：4,821 KB
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• 作者单位：Andrej Perdih (1) (2)
  Martina Hrast (3)
  Kaja Pureber (1) (4)
  Hélène Barreteau (5)
  Simona Goli? Grdadolnik (1) (4)
  Darko Kocjan (1) (4)
  Stanislav Gobec (3)
  Tom Solmajer (1)
  Gerhard Wolber (2)
  
  1. National Institute of Chemistry, Hajdrihova 19, 1001, Ljubljana, Slovenia
  2. Institute of Pharmacy, Freie Universit?t Berlin, K?nigin Luise-Strasse 2+4, 14195, Berlin, Germany
  3. Faculty of Pharmacy, University of Ljubljana, A?ker?eva 7, 1001, Ljubljana, Slovenia
  4. EN-FIST Centre of Excellence, Trg Osvobodilne fronte 13, 1000, Ljubljana, Slovenia
  5. Laboratoire des Enveloppes Bactériennes et Antibiotiques, IBBMC, Université Paris-Sud, 91405, Orsay, France
  
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Physical Chemistry
  Computer Applications in Chemistry
  Animal Anatomy, Morphology and Histology
  
• 出版者：Springer Netherlands
• ISSN：1573-4951

文摘

Bacterial resistance to the available antibiotic agents underlines an urgent need for the discovery of novel antibacterial agents. Members of the bacterial Mur ligase family MurC–MurF involved in the intracellular stages of the bacterial peptidoglycan biosynthesis have recently emerged as a collection of attractive targets for novel antibacterial drug design. In this study, we have first extended the knowledge of the class of furan-based benzene-1,3-dicarboxylic acid derivatives by first showing a multiple MurC–MurF ligase inhibition for representatives of the extended series of this class. Steady-state kinetics studies on the MurD enzyme were performed for compound 1, suggesting a competitive inhibition with respect to ATP. To the best of our knowledge, compound 1 represents the first ATP-competitive MurD inhibitor reported to date with concurrent multiple inhibition of all four Mur ligases (MurC–MurF). Subsequent molecular dynamic (MD) simulations coupled with interaction energy calculations were performed for two alternative in silico models of compound 1 in the UMA/d-Glu- and ATP-binding sites of MurD, identifying binding in the ATP-binding site as energetically more favorable in comparison to the UMA/d-Glu-binding site, which was in agreement with steady-state kinetic data. In the final stage, based on the obtained MD data novel furan-based benzene monocarboxylic acid derivatives 8-strong class="EmphasisTypeBold">11, exhibiting multiple Mur ligase (MurC–MurF) inhibition with predominantly superior ligase inhibition over the original series, were discovered and for compound 10 it was shown to possess promising antibacterial activity against S. aureus. These compounds represent novel leads that could by further optimization pave the way to novel antibacterial agents.