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Novel naphthalene-N-sulfonyl-D-glutamic acid derivatives as inhibitors of MurD, a key peptidoglycan biosynthesis enzyme.

Humljan J, Kotnik M, Contreras-Martel C, Blanot D, Urleb U, Dessen A, Solmajer T, Gobec S
J Med Chem 51 7486-94 (2008)
Related entries: 2uuo, 2uup, 2vtd

Cited: 35 times
EuropePMC logo PMID: 19007109

Abstract

Mur ligases have essential roles in the biosynthesis of peptidoglycan, and they represent attractive targets for the design of novel antibacterials. MurD (UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase) is the second enzyme in the series of Mur ligases, and it catalyzes the addition of D-glutamic acid (D-Glu) to the cytoplasmic intermediate UDP-N-acetylmuramoyl-L-alanine (UMA). Because of the high binding affinity of D-Glu toward MurD, we synthesized and biochemically evaluated a series of N-substituted D-Glu derivatives as potential inhibitors of MurD from E. coli, which allowed us to explore the structure-activity relationships.The substituted naphthalene-N-sulfonyl-D-Glu inhibitors, which were synthesized as potential transition state analogues, displayed IC50 values ranging from 80 to 600 microM. In addition, the high-resolution crystal structures of MurD in complex with four novel inhibitors revealed details of the binding mode of the inhibitors within the active site of MurD. Structure-activity relationships and cocrystal structures constitute an excellent starting point for further development of novel MurD inhibitors of this structural class.

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  1. Inhibitors of the peptidoglycan biosynthesis enzymes MurA-F. Hrast M, Sosič I, Sink R, Gobec S. Bioorg Chem 55 2-15 (2014)
  2. Peptidoglycan biosynthesis machinery: a rich source of drug targets. Gautam A, Vyas R, Tewari R. Crit Rev Biotechnol 31 295-336 (2011)
  3. The biology of Mur ligases as an antibacterial target. Kouidmi I, Levesque RC, Paradis-Bleau C. Mol Microbiol 94 242-253 (2014)
  4. Amino Acid Based Antimicrobial Agents - Synthesis and Properties. Nowak MG, Skwarecki AS, Milewska MJ. ChemMedChem 16 3513-3544 (2021)
  5. The Role of Organosulfur Compounds as Nrf2 Activators and Their Antioxidant Effects. Egbujor MC, Petrosino M, Zuhra K, Saso L. Antioxidants (Basel) 11 1255 (2022)
  6. Recent developments on UDP-N-acetylmuramoyl-L-alanine-D-gutamate ligase (Mur D) enzyme for antimicrobial drug development: An emphasis on in-silico approaches. Gaur V, Bera S. Curr Res Pharmacol Drug Discov 3 100137 (2022)
  7. Antibiotics and Antibiotic Resistance-Mur Ligases as an Antibacterial Target. Hervin V, Roy V, Agrofoglio LA. Molecules 28 8076 (2023)
  8. Breaking down the cell wall: Still an attractive antibacterial strategy. Zhou J, Cai Y, Liu Y, An H, Deng K, Ashraf MA, Zou L, Wang J. Front Microbiol 13 952633 (2022)
  9. Peptidoglycan pathways: there are still more! Helal AM, Sayed AM, Omara M, Elsebaei MM, Mayhoub AS. RSC Adv 9 28171-28185 (2019)

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  2. Discovery of novel benzene 1,3-dicarboxylic acid inhibitors of bacterial MurD and MurE ligases by structure-based virtual screening approach. Perdih A, Kovac A, Wolber G, Blanot D, Gobec S, Solmajer T. Bioorg Med Chem Lett 19 2668-2673 (2009)
  3. In silico identification of common putative drug targets in Leptospira interrogans. Amineni U, Pradhan D, Marisetty H. J Chem Biol 3 165-173 (2010)
  4. Preparation of arylsulfonyl chlorides by chlorosulfonylation of in situ generated diazonium salts using a continuous flow reactor. Malet-Sanz L, Madrzak J, Ley SV, Baxendale IR. Org Biomol Chem 8 5324-5332 (2010)
  5. 5-Benzylidenethiazolidin-4-ones as multitarget inhibitors of bacterial Mur ligases. Tomasić T, Zidar N, Kovac A, Turk S, Simcic M, Blanot D, Müller-Premru M, Filipic M, Grdadolnik SG, Zega A, Anderluh M, Gobec S, Kikelj D, Peterlin Masic L. ChemMedChem 5 286-295 (2010)
  6. MreB and MurG as scaffolds for the cytoplasmic steps of peptidoglycan biosynthesis. Favini-Stabile S, Contreras-Martel C, Thielens N, Dessen A. Environ Microbiol 15 3218-3228 (2013)
  7. Binding free energy calculations of N-sulphonyl-glutamic acid inhibitors of MurD ligase. Perdih A, Bren U, Solmajer T. J Mol Model 15 983-996 (2009)
  8. New noncovalent inhibitors of penicillin-binding proteins from penicillin-resistant bacteria. Turk S, Verlaine O, Gerards T, Zivec M, Humljan J, Sosič I, Amoroso A, Zervosen A, Luxen A, Joris B, Gobec S. PLoS One 6 e19418 (2011)
  9. Dual Inhibitor of MurD and MurE Ligases from Escherichia coli and Staphylococcus aureus. Tomašić T, Sink R, Zidar N, Fic A, Contreras-Martel C, Dessen A, Patin D, Blanot D, Müller-Premru M, Gobec S, Zega A, Kikelj D, Mašič LP. ACS Med Chem Lett 3 626-630 (2012)
  10. Second-generation sulfonamide inhibitors of D-glutamic acid-adding enzyme: activity optimisation with conformationally rigid analogues of D-glutamic acid. Sosič I, Barreteau H, Simčič M, Sink R, Cesar J, Zega A, Grdadolnik SG, Contreras-Martel C, Dessen A, Amoroso A, Joris B, Blanot D, Gobec S. Eur J Med Chem 46 2880-2894 (2011)
  11. Phosphorylated hydroxyethylamines as novel inhibitors of the bacterial cell wall biosynthesis enzymes MurC to MurF. Sova M, Kovac A, Turk S, Hrast M, Blanot D, Gobec S. Bioorg Chem 37 217-222 (2009)
  12. Virtual screening for potential inhibitors of homology modeled Leptospira interrogans MurD ligase. Umamaheswari A, Pradhan D, Hemanthkumar M. J Chem Biol 3 175-187 (2010)
  13. Benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole derivatives as multiple inhibitors of bacterial Mur ligases (MurC-MurF). Perdih A, Hrast M, Barreteau H, Gobec S, Wolber G, Solmajer T. Bioorg Med Chem 22 4124-4134 (2014)
  14. Selective Late-Stage Sulfonyl Chloride Formation from Sulfonamides Enabled by Pyry-BF4. Gómez-Palomino A, Cornella J. Angew Chem Int Ed Engl 58 18235-18239 (2019)
  15. Synthesis of ureidomuraymycidine derivatives for structure-activity relationship studies of muraymycins. Aleiwi BA, Schneider CM, Kurosu M. J Org Chem 77 3859-3867 (2012)
  16. Structure-Based Pharmacophores for Virtual Screening. Löwer M, Proschak E. Mol Inform 30 398-404 (2011)
  17. Improved synthesis of capuramycin and its analogues. Wang Y, Siricilla S, Aleiwi BA, Kurosu M. Chemistry 19 13847-13858 (2013)
  18. Crystallographic Study of Peptidoglycan Biosynthesis Enzyme MurD: Domain Movement Revisited. Šink R, Kotnik M, Zega A, Barreteau H, Gobec S, Blanot D, Dessen A, Contreras-Martel C. PLoS One 11 e0152075 (2016)
  19. The binding mode of second-generation sulfonamide inhibitors of MurD: clues for rational design of potent MurD inhibitors. Simčič M, Sosič I, Hodošček M, Barreteau H, Blanot D, Gobec S, Grdadolnik SG. PLoS One 7 e52817 (2012)
  20. Combining molecular docking and molecular dynamics studies for modelling Staphylococcus aureus MurD inhibitory activity. Azam MA, Jupudi S, Saha N, Paul RK. SAR QSAR Environ Res 30 1-20 (2019)
  21. Homology modeling, molecular dynamics and inhibitor binding study on MurD ligase of Mycobacterium tuberculosis. Arvind A, Kumar V, Saravanan P, Mohan CG. Interdiscip Sci 4 223-238 (2012)
  22. Multi-targeted therapy for leprosy: insilico strategy to overcome multi drug resistance and to improve therapeutic efficacy. Anusuya S, Natarajan J. Infect Genet Evol 12 1899-1910 (2012)
  23. New high-throughput fluorimetric assay for discovering inhibitors of UDP-N-acetylmuramyl-L-alanine: D-glutamate (MurD) ligase. Kristan K, Kotnik M, Oblak M, Urleb U. J Biomol Screen 14 412-418 (2009)
  24. Extra precision docking, free energy calculation and molecular dynamics studies on glutamic acid derivatives as MurD inhibitors. Azam MA, Jupudi S. Comput Biol Chem 69 55-63 (2017)
  25. Identification of Potential Inhibitors of MurD Enzyme of Staphylococcus aureus from a Marine Natural Product Library. Zheng X, Zheng T, Liao Y, Luo L. Molecules 26 6426 (2021)


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