[en] D-Glutamic acid-adding enzyme (MurD) catalyses the essential addition of d-glutamic acid to the cytoplasmic peptidoglycan precursor UDP-N-acetylmuramoyl-l-alanine, and as such it represents an important antibacterial drug-discovery target enzyme. Based on a series of naphthalene-N-sulfonyl-d-Glu derivatives synthesised recently, we synthesised two series of new, optimised sulfonamide inhibitors of MurD that incorporate rigidified mimetics of d-Glu. The compounds that contained either constrained d-Glu or related rigid d-Glu mimetics showed significantly better inhibitory activities than the parent compounds, thereby confirming the advantage of molecular rigidisation in the design of MurD inhibitors. The binding modes of the best inhibitors were examined with high-resolution NMR spectroscopy and X-ray crystallography. We have solved a new crystal structure of the complex of MurD with an inhibitor bearing a 4-aminocyclohexane-1,3-dicarboxyl moiety. These data provide an additional step towards the development of sulfonamide inhibitors with potential antibacterial activities.
Disciplines :
Microbiology
Author, co-author :
Sosic, Izidor
Barreteau, Helene
Simcic, Mihael
Sink, Roman
Cesar, Jozko
Zega, Anamarija
Grdadolnik, Simona Golic
Contreras-Martel, Carlos
Dessen, Andrea
Amoroso, Ana Maria ; Université de Liège > Département des sciences de la vie > Centre d'ingénierie des protéines
Joris, Bernard ; Université de Liège > Département des sciences de la vie > Physiologie et génétique bactériennes
H.W. Boucher, G.H. Talbot, J.S. Bradley, J.E. Edwards Jr., D. Gilbert, L.B. Rice, M. Scheld, B. Spellberg, and J. Bartlett Clin. Infect. Dis. 48 2009 1 12
I. Chopra, C. Schofield, M. Everett, A. O'Neill, K. Miller, M. Wilcox, J.M. Frre, M. Dawson, L. Czaplewski, U. Urleb, and P. Courvalin Lancet Infect. Dis. 8 2008 133 139
W. Vollmer, D. Blanot, and M.A. de Pedro FEMS Microbiol. Rev. 32 2008 149 167
H. Barreteau, A. Kovač, A. Boniface, M. Sova, S. Gobec, and D. Blanot FEMS Microbiol. Rev. 32 2008 168 207
A. Bouhss, S. Dementin, J. van Heijenoort, C. Parquet, and D. Blanot Method. Enzymol. 354 2002 189 196
M. Ikeda, M. Wachi, H.K. Jung, F. Ishino, and M. Matsunashi J. Gen. Appl. Microbiol. 36 1990 179 187
A. Bouhss, D. Mengin-Lecreulx, D. Blanot, J. van Heijenoort, and C. Parquet Biochemistry 36 1997 11556 11563
S.S. Eveland, D.L. Pompliano, and M.S. Anderson Biochemistry 36 1997 6223 6229
A. Bouhss, S. Dementin, C. Parquet, D. Mengin-Lecreulx, J.A. Bertrand, D. Le Beller, O. Dideberg, J. van Heijenoort, and D. Blanot Biochemistry 38 1999 12240 12247
C.A. Smith J. Mol. Biol. 362 2006 640 655
J.A. Bertrand, G. Auger, L. Martin, E. Fanchon, D. Blanot, D. Le Beller, J. van Heijenoort, and O. Dideberg J. Mol. Biol. 289 1999 579 590
J.A. Bertrand, G. Auger, E. Fanchon, L. Martin, D. Blanot, J. van Heijenoort, and O. Dideberg EMBO J. 16 1997 3416 3425
J.A. Bertrand, E. Fanchon, L. Martin, L. Chantalat, G. Auger, D. Blanot, J. van Heijenoort, and O. Dideberg J. Mol. Biol. 301 2000 1257 1266
Y. Yan, S. Munshi, B. Leiting, M.S. Anderson, J. Chrzas, and Z. Chen J. Mol. Biol. 304 2000 435 445
R. Šink, A. Kovač, T. Tomašić, V. Rupnik, A. Boniface, J. Bostock, I. Chopra, D. Blanot, L. Peterlin-Mašič, S. Gobec, and A. Zega Chem. Med. Chem. 3 2008 1362 1370
J.R. Horton, J.M. Bostock, I. Chopra, L. Hesse, S.E.V. Phillips, D.J. Adams, A.P. Johnson, and C.W.G. Fishwick Bioorg. Med. Chem. Lett. 13 2003 1557 1560
C. Paradis-Bleau, M. Beaumont, L. Boudreault, A. Lloyd, F. Sanschagrin, T.D.H. Bugg, and R.C. Levesque Peptides 27 2006 1693 1700
Z. Li, G.D. Francisco, W. Hu, P. Labthavikul, P.J. Petersen, A. Severin, G. Singh, Y. Yang, B.A. Rasmussen, Y.I. Lin, J.S. Skotnicki, and T. Mansour Bioorg. Med. Chem. Lett. 13 2003 2591 2594
S. Antane, C.E. Caufield, W. Hu, D. Keeney, P. Labthavikul, K. Morris, S.M. Naughton, P.J. Petersen, B.A. Rasmussen, G. Singh, and Y. Yang Bioorg. Med. Chem. Lett. 16 2006 176 180
S. Turk, A. Kovač, A. Boniface, J.M. Bostock, I. Chopra, D. Blanot, and S. Gobec Bioorg. Med. Chem. 17 2009 1884 1889
K. Kristan, M. Kotnik, M. Oblak, and U. Urleb J. Biomol. Screen. 14 2009 412 418
M. Kotnik, J. Humljan, C. Contreras-Martel, M. Oblak, K. Kristan, M. Hervé, D. Blanot, U. Urleb, S. Gobec, A. Dessen, and T. Šolmajer J. Mol. Biol. 370 2007 107 115
T. Tomašić, N. Zidar, V. Rupnik, A. Kovač, D. Blanot, S. Gobec, D. Kikelj, and L. Peterlin-Maši&ccaron Bioorg. Med. Chem. Lett. 19 2009 153 157
J. Humljan, M. Kotnik, C. Contreras-Martel, D. Blanot, U. Urleb, A. Dessen, T. Šolmajer, and S. Gobec J. Med. Chem. 51 2008 7486 7494
M. Simčič, M. Hodošček, J. Humljan, K. Kristan, U. Urleb, D. Kocjan, and S. Grdadolnik-Golič J. Med. Chem. 52 2009 2899 2908
D. Motiejunas, and R.C. Wade Structural, energetic, and dynamic aspects of ligand-receptor interactions D.J. Triggle, J.B. Taylor, Comprehensive Medicinal Chemistry II vol. 4 2007 Elsevier Oxford 193 213
V. Škarić, B. Djuras, and V. Turjak-Zebić J. Chem. Soc. Perkin Trans. 1 1975 1959 1961
A.F. Abdel-Magid, K.G. Carson, B.D. Harris, C.A. Maryanoff, and R.D. Shah J. Org. Chem. 61 1996 3849 3862
C. Wolf, S. Liu, X. Mei, A.T. August, and M.D. Casimir J. Org. Chem. 71 2006 3270 3273
A. Padwa, M. Dimitroff, A.G. Waterson, and T. Wu J. Org. Chem. 62 1997 4088 4096
A. Perdih, A. Kovač, G. Wolber, D. Blanot, S. Gobec, and T. Solmajer Bioorg. Med. Chem. Lett. 19 2009 2668 2673
P.J. Hajduk, D.D. Augeri, J. Mack, R. Mendoza, J. Yang, S.F. Betz, and S.W. Fesik J. Am. Chem. Soc. 122 2000 7898 7904
G. Auger, L. Martin, J. Bertrand, P. Ferrari, E. Fanchon, S. Vaganay, Y. Pétillot, J. van Heijenoort, D. Blanot, and O. Dideberg Protein Expr. Purif. 13 1998 23 29
European Committee for Antimicrobial Susceptibility Testing (EUCAST) Determination of minimum inhibitory concentrations (MICs) of antibacterial agents by broth dilution Clin. Microbiol. Infect. 9 2003 1 7
Clinical Laboratory Standards Institute (CLSI) M07-A8 eighth ed. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard vol. 29 (2) 2009 pp. 1-65
L. Kay, P. Keifer, and T. Saarinen J. Am. Chem. Soc. 114 1992 10663 10665
F. Delaglio, S. Grzesiek, G.W. Vuister, G. Zhu, J. Pfeifer, and A. Bax J. Biomol. NMR 6 1995 277 293
T.D. Goddard, D.G. Kneller, SPARKY 3, University of California, San Francisco.
F.H. Schumann, H. Riepl, T. Maurer, W. Gronwald, P. K-Neidig, and H.R. Kalbitzer J. Biomol. NMR 39 2007 275 289
S.E. Cellitti, D.H. Jones, L. Lagpacan, X. Hao, Q. Zhang, H. Hu, S.M. Brittain, A. Brinker, J. Caldwell, B. Bursulaya, G. Spraggon, A. Brock, Y. Ryu, T. Uno, P.G. Schultz, and B.H. Geierstanger J. Am. Chem. Soc. 130 2008 9268 9281
