User menu

Accès à distance ? S'identifier sur le proxy UCLouvain

12- to 22-membered bridged β-lactams as potential penicillin-binding protein inhibitors

Primary tabs

Sliwa, Aline [UCL] Dive, G. [ULg] Marchand-Brynaert, Jacqueline [UCL]

As potential inhibitors of penicillin-binding proteins (PBPs), we focused our research on the synthesis of non-traditional 1,3-bridged β-lactams embedded into macrocycles. We synthesized 12- to 22-membered bicyclic β-lactams by the ring-closing metathesis (RCM) of bis-Ï-alkenyl-3(S)- aminoazetidinone precursors. The reactivity of 1,3-bridged β-lactams was estimated by the determination of the energy barrier of a concerted nucleophilic attack and lactam ring-opening process by using ab initio calculations. The results predicted that 16-membered cycles should be more reactive. Biochemical evaluations against R39 DD-peptidase and two resistant PBPs, namely, PBP2a and PBP5, revealed the inhibition effect of compound 4 d, which featured a 16-membered bridge and the N-tert-butyloxycarbonyl chain at the C3 position of the β-lactam ring. Surprisingly, the corresponding bicycle, 12 d, with the PhOCH 2CO side chain at C3 was inactive. Reaction models of the R39 active site gave a new insight into the geometric requirements of the conformation of potential ligands and their steric hindrance; this could help in the design of new compounds. Bridging inhibition: A series of 12- to 22-membered bicyclic bridged β-lactams were synthesized with the aim of developing new inhibitors of penicillin-binding proteins and feature a planar amide function and no carboxy group (see picture; Boc=tert-butyloxycarbonyl). © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2012
Language Anglais
Journal information "Chemistry - An Asian Journal" - Vol. 7, no.2, p. 425-434 (2012)
Peer reviewed yes
Publisher Wiley
issn 1861-4728
Publication status Publié
Affiliation UCL - SST/IMCN/MOST - Molecules, Solids and Reactivity
Keywords Ab initio calculations ; Macrocycles ; Metathesis ; Non-traditional ; Nucleophilic attack ; Penicillin-binding proteins ; Potential inhibitors ; Potential ligand ; Reaction model ; Ring closing metathesis ; Ring opening ; Enzymes ; Side-chains ; Steric hindrances ; Biosynthesis ; Calculations ; Corrosion inhibitors ; Enzymes ; Proteins ; Amides ; Inhibitors ; Macrocycles ; Metathesis ; Ab initio calculations ; Active site ; Carboxy groups ; Inhibition effect
Links
  1. ABRAHAM E. P., CHAIN E., An Enzyme from Bacteria able to Destroy Penicillin, 10.1038/146837a0
  2. Walsh Christopher, 10.1038/35021219
  3. Livermore D. M., Has the era of untreatable infections arrived?, 10.1093/jac/dkp255
  4. French G.L., The continuing crisis in antibiotic resistance, 10.1016/s0924-8579(10)70003-0
  5. Hubschwerlen C., β-Lactam Antibiotics, Comprehensive Medicinal Chemistry II (2007) ISBN:9780080450445 p.479-518, 10.1016/b0-08-045044-x/00218-2
  6. Strominger Jack L., Enzymatic Reactions in Bacterial Cell Wall Synthesis Sensitive to Penicillins, Cephalosporins, and Other Antibacterial Agents, Antibiotics (1967) ISBN:9783662376492 p.705-713, 10.1007/978-3-662-38439-8_62
  7. Woodward, The Chemistry of Penicillin, 440 (1949)
  8. Alcaide B., Aragoncillo C., Almendros P., Cephalosporins, Comprehensive Heterocyclic Chemistry III (2008) ISBN:9780080449920 p.111-171, 10.1016/b978-008044992-0.00202-9
  9. Marchand-Brynaert J., Brulé C., Penicillins, Comprehensive Heterocyclic Chemistry III (2008) ISBN:9780080449920 p.173-237, 10.1016/b978-008044992-0.00203-0
  10. Bassetti Matteo, Nicolini Laura, Esposito Silvano, Righi Elda, Viscoli Claudio, Current Status of Newer Carbapenems, 10.2174/092986709787458498
  11. Llarrull Leticia I, Testero Sebastian A, Fisher Jed F, Mobashery Shahriar, The future of the β-lactams, 10.1016/j.mib.2010.09.008
  12. Bassetti, Crit. Care, 15 (2011)
  13. Urbach Allan, Dive Georges, Marchand-Brynaert Jacqueline, Novel Large-Ring 1,3-Bridged 2-Azetidinones as Potential Inhibitors of Penicillin-Binding Proteins, 10.1002/ejoc.200801193
  14. Urbach Allan, Dive Georges, Tinant Bernard, Duval Valérie, Marchand-Brynaert Jacqueline, Large ring 1,3-bridged 2-azetidinones: Experimental and theoretical studies, 10.1016/j.ejmech.2008.10.016
  15. Sliwa Aline, Dive Georges, Habib Jiwan Jean-Louis, Marchand-Brynaert Jacqueline, Cyclodimerization by ring-closing metathesis: synthesis, computational, and biological evaluation of novel bis-azetidinyl-macrocycles, 10.1016/j.tet.2010.10.015
  16. Magn. Reson. Chem. 2011
  17. Sauvage Eric, Herman Raphaël, Petrella Stephanie, Duez Colette, Bouillenne Fabrice, Frère Jean-Marie, Charlier Paulette, Crystal Structure of theActinomaduraR39 DD-peptidase Reveals New Domains in Penicillin-binding Proteins, 10.1074/jbc.m503271200
  18. Sauvage Eric, Powell Ailsa J., Heilemann Jason, Josephine Helen R., Charlier Paulette, Davies Christopher, Pratt R.F., Crystal Structures of Complexes of Bacterial dd-Peptidases with Peptidoglycan-Mimetic Ligands: The Substrate Specificity Puzzle, 10.1016/j.jmb.2008.06.012
  19. Lim, Nat. Struct. Biol., 9, 870 (2002)
  20. Sauvage E., Kerff F., Fonzé E., Herman R., Schoot B., Marquette J.-P., Taburet Y., Prevost D., Dumas J., Leonard G., Stefanic P., Coyette J., Charlier P., The 2.4-Å crystal structure of the penicillin-resistant penicillin-binding protein PBP5fm from Enterococcus faecium in complex with benzylpenicillin, 10.1007/s00018-002-8500-0
  21. Jih Ru Hwu, Jain Moti L., Shwu-Chen Tsay, Hakimelahi Gholam H., Ceric ammonium nitrate in the deprotection of tert-butoxycarbonyl group, 10.1016/0040-4039(96)00211-0
  22. Olah George A., Narang Subhash C., Gupta B. G. Balaram, Malhotra Ripudaman, Synthetic methods and reactions. 62. Transformations with chlorotrimethylsilane/sodium iodide, a convenient in situ iodotrimethylsilane reagent, 10.1021/jo01322a012
  23. Miller Marvin J., Mattingly Phillip G., Morrison Marjorie A., Kerwin James F., Synthesis of .beta.-lactams from substituted hydroxamic acids, 10.1021/ja00543a021
  24. Tatewaki Hiroshi, Huzinaga Sigeru, A systematic preparation of new contracted Gaussian-type orbital sets. III. Second-row atoms from Li through ne, 10.1002/jcc.540010302
  25. Dive G., Dehareng D., Ghuysen J. M., Energy analysis on small to medium sized H-bonded complexes, 10.1007/bf01112981
  26. Dive G., Dehareng D., Serine peptidase catalytic machinery: Cooperative one-step mechanism, 10.1002/(sici)1097-461x(1999)73:2<161::aid-qua10>3.0.co;2-e
  27. Schwyzer R., Hürlimann Ch., Coenzym A: Modellreaktionen zur enzymatischen Aktivierung von Acylderivaten des Coenzyms A, 10.1002/hlca.19540370119
  28. Adam M, Damblon C, Jamin M, Zorzi W, Dusart V, Galleni M, el Kharroubi A, Piras G, Spratt B G, Keck W, Acyltransferase activities of the high-molecular-mass essential penicillin-binding proteins, 10.1042/bj2790601
  29. N D
  30. Sader H??lio S., Gales Ana C., Emerging Strategies in Infectious Diseases : New Carbapenem and Trinem Antibacterial Agents, 10.2165/00003495-200161050-00001
  31. 2004
  32. Feng Brian Y, Shoichet Brian K, A detergent-based assay for the detection of promiscuous inhibitors, 10.1038/nprot.2006.77
  33. Lakaye B, Damblon C, Jamin M, Galleni M, Lepage S, Joris B, Marchand-Brynaert J, Frydrych C, Frere J M, Synthesis, purification and kinetic properties of fluorescein-labelled penicillins, 10.1042/bj3000141
  34. Zervosen A., Lu W.-P., Chen Z., White R. E., Demuth T. P., Frere J.-M., Interactions between Penicillin-Binding Proteins (PBPs) and Two Novel Classes of PBP Inhibitors, Arylalkylidene Rhodanines and Arylalkylidene Iminothiazolidin-4-ones, 10.1128/aac.48.3.961-969.2004
Bibliographic reference Sliwa, Aline ; Dive, G. ; Marchand-Brynaert, Jacqueline. 12- to 22-membered bridged β-lactams as potential penicillin-binding protein inhibitors. In: Chemistry - An Asian Journal, Vol. 7, no.2, p. 425-434 (2012)
Permanent URL http://hdl.handle.net/2078.1/124448