Discovery of LFF571: An investigational agent for Clostridium difficile infection

Journal of Medicinal Chemistry

Volumn 55, Issue 5, 2012, Pages 2376-2387

  Lamarche, Matthew J ^a   Leeds, Jennifer A ^a   Amaral, Adam ^a   Brewer, Jason T ^a   Bushell, Simon M ^a   Deng, Gejing ^a   Dewhurst, Janetta M ^a   Ding, Jian ^a   Dzink Fox, Joanne ^a   Gamber, Gabriel ^a   Jain, Akash ^b   Lee, Kwangho ^a   Lee, Lac ^a   Lister, Troy ^a   McKenney, David ^a   Mullin, Steve ^a   Osborne, Colin ^a   Palestrant, Deborah ^a   Patane, Michael A ^a   Rann, Elin M ^a   Sachdeva, Meena ^a   Shao, Jian ^a   Tiamfook, Stacey ^a   Trzasko, Anna ^a   Whitehead, Lewis ^a   Yifru, Aregahegn ^a   Yu, Donghui ^a   Yan, Wanlin ^a   Zhu, Qingming ^a   more..

^a NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

^b NOVARTIS PHARMA AG   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBIOTIC AGENT; DICARBOXYLIC ACID DERIVATIVE; GE 2270A; LFF 571; LFF571; NATURAL PRODUCT; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIBACTERIAL ACTIVITY; CLOSTRIDIUM DIFFICILE INFECTION; CONTROLLED STUDY; CRYSTALLOGRAPHY; DISEASE MODEL; DRUG EFFICACY; DRUG SOLUBILITY; FEMALE; MALE; MOUSE; NONHUMAN; RAT; REVIEW; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTI-BACTERIAL AGENTS; CLOSTRIDIUM DIFFICILE; CRICETINAE; CRYSTALLOGRAPHY, X-RAY; ENTEROCOCCUS; ENTEROCOLITIS, PSEUDOMEMBRANOUS; ESCHERICHIA COLI PROTEINS; FEMALE; MALE; MESOCRICETUS; MICE; MICROBIAL SENSITIVITY TESTS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PEPTIDE ELONGATION FACTOR TU; RATS; RATS, SPRAGUE-DAWLEY; SOLUBILITY; STAPHYLOCOCCUS AUREUS; STREPTOCOCCUS PYOGENES; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES; WATER;

EID: 84863288432     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm201685h     Document Type: Review

References (27)

1. Gerding, D. N.; Muto, C. A.; Owens, R. C., Jr. Treatment of Clostridium difficile infection Clin. Infect. Dis. 2008, 46 (Suppl. 1) S32-S42
2. Loo, V. G.; Poirier, L.; Miller, M. A.; Oughton, M.; Libman, M. D.; Michaud, S.; Bourgault, A.-M.; Nguyen, T.; Frenette, C.; Kelly, M.; Vibien, A.; Brassard, P.; Fenn, S.; Dewar, K.; Hudson, T. J.; Horn, R.; René, P.; Monczak, Y.; Dascal, A. A predominantly clonal multi-institutional outbreak of Clostridium difficile -associated diarrhea with high morbidity and mortality N. Engl. J. Med. 2005, 353, 2442-2449
3. McDonald, L. C.; Killgore, G. E.; Thompson, A; Owens, R. C., Jr.; Kazakova, S. V.; Sambol, S. P.; Johnson, S; Gerding, D. N. An epidemic, toxin gene-variant strain of Clostridium difficile N. Engl. J. Med. 2005, 353, 2433-2441
4. McDonald, L. C.; Owings, M; Jernigan, D. B. Clostridium difficile infection in patients discharged from US short-stay hospitals, 1996-2003 Emerging Infect. Dis. 2006, 12 (3) 409-415
5. Redelings, M. D.; Sorvillo, F.; Mascola, L. Increase in Clostridium difficile -related mortality rates, United States, 1999-2004 Emerging Infect. Dis. 2007, 13, 1417-1419
6. Dubberke, E. R.; Reske, K. A.; Olsen, M. A.; McDonald, L. C.; Fraser, V. J. Short and long-term attributable costs of Clostridium difficile -associated disease in nonsurgical inpatients Clin. Infect. Dis. 2008, 46, 497
7. Louie, T. J.; Miller, M. A.; Mullane, K. M.; Weiss, K.; Lentnek, A.; Golan, Y.; Gorbach, S.; Sears, P.; Shue, Y.-K. Fidaxomicin versus vancomycin for Clostridium difficile infection N. Engl. J. Med. 2011, 364, 422-431
8. Kelly, C. P.; LaMont, J. T. Clostridium difficile -more difficult than ever N. Engl. J. Med. 2008, 359 (18) 1932-1940
9. Poulakou, G.; Giamarellou, H. Investigational treatments for postoperative surgical site infections Expert Opin. Invest. Drugs 2007, 16 (2) 137-155
10. von Nussbaum, F.; Brands, M.; Hinzen, B.; Weigand, S.; Habich, D. Antibacterial natural products in medicinal chemistry-exodus or revival? Angew. Chem., Int. Ed. 2006, 45, 5072-5129
11. Selva, E.; Beretta, G.; Montanini, N.; Saddler, G. S.; Gastaldo, L.; Ferrari, P.; Lorenzetti, R.; Landini, P.; Ripamonti, F.; Goldstein, B. P.; Berti, M.; Montanaro, I.; Denaro, M. Antibiotic GE2270 A: a novel inhibitor of protein synthesis J. Antibiot. 1991, 44 (7) 693-701
12. The structure was later corrected and verified: Tavecchia, P.; Gentili, P.; Kurz, M.; Sottani, C.; Bonfichi, R.; Selva, E.; Lociuro, S.; Restelli, E.; Ciabatti, R. Degradation studies of MDL62,879 (GE220 A) and revision of the structure Tetrahedron 1995, 51 (16) 4867-4890
13. LaMarche, M. J.; Leeds, J. A.; Dzink-Fox, J.; Gunderson, K.; Krastel, P.; Memmert, K.; Patane, M. A.; Rann, E. M.; Schmitt, E.; Tiamfook, S.; Wang, B. 4-Aminothiazolyl analogues of GE2270 A: antibacterial lead finding J. Med. Chem. 2011, 54, 2517-2521
14. LaMarche, M. J.; Leeds, J. A.; Dzink-Fox, J.; Mullin, S.; Patane, M. A.; Rann, E. M.; Tiamfook, S. 4-Aminothiazolyl analogues of GE2270 A: design, synthesis, and evaluation of imidazole analogs Bioorg. Med. Chem. Lett. 2011, 21 (11) 3210-3215
15. LaMarche, M. J.; Leeds, J. A.; Brewer, J. T.; Bushell, S. M.; Dewhurst, J. M.; Dzink-Fox, J.; Gangl, E.; Jain, A.; Mullin, S.; Neckermann, G.; Osborn, C.; Palestrant, D.; Patane, M. A.; Rann, E. M.; Sachdeva, M.; Shao, J.; Tiamfook, S.; Whitehead, L.; Yu, D. Antibacterial optimization of 4-aminothiazolyl analogues of GE2270 A: identification of the cycloalkylcarboxylic acids J. Med. Chem. 2011, 54, 8099-8109
16. Clough, J.; Chen, S.; Gordon, E. M.; Hackbarth, C.; Lam, S.; Trias, J.; White, R. J.; Candiani, G.; Donadio, S.; Romano, G.; Ciabatti, R.; Jacobs, J. W. Combinatorial modification of natural products: synthesis and in vitro analysis of derivatives of thiazole peptide antibiotic GE2270 A: a-ring modifications Bioorg. Med. Chem. Lett. 2003, 13, 3409-3414
17. Malabarba, M.; Cavaleri, M.; Mosconi, G.; Jabes, D.; Romano, G. Use of Amide Derivative of GE2270 Factor A3 for the Treatment of Acne. WO03105881, 2003.
18. MIC assays were conducted according to the Clinical and Laboratory Standards Institute (CLSI). Wikler, M. A.; Cockerill, F. R.; Bush, K. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard, 8 th ed.; CLSI M07-A8, Clinical and Laboratory Standards Institute: Wayne, PA, 2009; Vol. 29, No. 2.
19. Bacterial strains included E. faecalis (ATCC 29212), E. faecium (Prof. Chopra, University of Leeds U.K., strain 7130724), S. aureus (MRSA from Prof. Willinger, isolated from a pharyngeal smear, AKH Vienna A4.018), and S. pyogenes (ATCC BAA-595). Wikler, M. A.; Cockerill, F. R.; Bush, K. Performance Standards for Antimicrobial Susceptibility Testing; 19th Informational Supplement; CLSI M100-S19, Clinical and Laboratory Standards Institute: Wayne, PA, 2009; Vol. 29, No. 3. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria: Approved Standard M11-A7, 7 th ed.; Clinical and Laboratory Standards Institute: Wayne, PA; Vol. 27.
20. Zubay, G. In vitro synthesis of protein in microbial systems Annu. Rev. Genet. 1973, 7, 267-287
21. Zubay, G. Isolation and properties of CAP, the catabolite gene activator Methods Enzymol. 1980, 65, 856-877
22. Frimodt-Møller, N.; Knudesen, J. D.; Espersen, F. Handbook of Animal Models of Infection; Zak, O.; Sande, M. A., Eds.; Academic Press: San Diego, CA, 1999; pp 127-136.
23. Anton, P. M.; O'Brien, M; Kokkotou, E; Eisenstein, B; Michaelis, A; Rothstein, D; Paraschos, S; Kelly, C. P.; Pothoulakis, C. Rifalazil treats and prevents relapse of Clostridium difficile diarrhea in hamsters Antimicrob. Agents Chemother. 2004, 48, 3975-3979
24. Otwinowski, Z.; Minor, W. Processing of X-ray Diffraction Data Collected in Oscillation Mode. Macromolecular Crystallography. Part A; Carter, C.W., Jr.; Sweet, R. M., Eds.; Methods in Enzymology, Vol. 276; Academic Press: New York, 1997; pp 307-326.
25. McCoy, A. J.; Grosse-Kunstleve, R. W.; Adams, P. D.; Winn, M. D.; Storoni, L. C.; Read, R. J. Phaser crystallographic software J. Appl. Crystallogr. 2007, 40, 658-674
26. Brünger, A. T.; Adams, P. D.; Clore, G. M.; DeLano, W. L.; Gros, P; Grosse-Kunstleve, R. W.; Jiang, J. S.; Kuszewski, J.; Nilges, M.; Pannu, N. S.; Read, R. J.; Rice, L. M.; Simonson, T.; Warren, G. L. Crystallography & NMR system: a new software suite for macromolecular structure determination Acta Crystallogr., Sect. D: Biol. Crystallogr. 1998, 54 (Part 5) 905-921
27. Emsley, P; Cowtan, K. Coot: model-building tools for molecular graphics Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004, 60 (Part 12, No. 1) 2126-2132