This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Domínguez, J. M.
Right arrow Articles by Martín, J. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Domínguez, J. M.
Right arrow Articles by Martín, J. J.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, September 1998, p. 2274-2278, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Sordarins: A New Class of Antifungals with Selective Inhibition of the Protein Synthesis Elongation Cycle in Yeasts

Juan Manuel Domínguez,1 Valerie A. Kelly,2 Oonagh S. Kinsman,2 Michael S. Marriott,2 Federico Gómez de las Heras,1 and J. Julio Martín1,*

Departamento de Investigación, Glaxo Wellcome S.A., 28760-Tres Cantos, Madrid, Spain,1 and Glaxo Wellcome Research and Development, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, United Kingdom2

Received 16 January 1998/Returned for modification 20 April 1998/Accepted 24 June 1998

GR135402, a sordarin derivative, was isolated in an antifungal screening program. GR135402, sordarin, and derivatives of both compounds were evaluated for their ability to inhibit cell-free translational systems from five different pathogenic fungi (Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, and Cryptococcus neoformans). The activity profile of GR135402 is extended to other chemical compounds derived from sordarin. Experimental results indicate that sordarin analogs exert their antifungal effects by specifically inhibiting the protein synthesis elongation cycle in yeasts but do not affect protein synthesis machinery in mammalian systems. Intrinsically resistant strains owe their resistance to differences in the molecular target of sordarins in these strains. Preliminary studies performed to elucidate the mode of action of this new class of antifungal agents have shown that the putative target of sordarins is one of the protein synthesis elongation factors.

* Corresponding author. Mailing address: Departamento de Investigación, Glaxo Wellcome S.A., C/Severo Ochoa 2, 28760-Tres Cantos, Madrid, Spain. Phone: 34 91 8070301. Fax: 34 91 8070595. E-mail: jjmp28182{at}GlaxoWellcome.co.uk.

Antimicrobial Agents and Chemotherapy, September 1998, p. 2274-2278, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Andres, M. T., Viejo-Diaz, M., Fierro, J. F. (2008). Human Lactoferrin Induces Apoptosis-Like Cell Death in Candida albicans: Critical Role of K+-Channel-Mediated K+ Efflux. Antimicrob. Agents Chemother. 52: 4081-4088 [Abstract] [Full Text]  
  • Botet, J., Rodriguez-Mateos, M., Ballesta, J. P. G., Revuelta, J. L., Remacha, M. (2008). A Chemical Genomic Screen in Saccharomyces cerevisiae Reveals a Role for Diphthamidation of Translation Elongation Factor 2 in Inhibition of Protein Synthesis by Sordarin. Antimicrob. Agents Chemother. 52: 1623-1629 [Abstract] [Full Text]  
  • Soe, R., Mosley, R. T., Justice, M., Nielsen-Kahn, J., Shastry, M., Merrill, A. R., Andersen, G. R. (2007). Sordarin Derivatives Induce a Novel Conformation of the Yeast Ribosome Translocation Factor eEF2. J. Biol. Chem. 282: 657-666 [Abstract] [Full Text]  
  • Roman, E., Nombela, C., Pla, J. (2005). The Sho1 Adaptor Protein Links Oxidative Stress to Morphogenesis and Cell Wall Biosynthesis in the Fungal Pathogen Candida albicans. Mol. Cell. Biol. 25: 10611-10627 [Abstract] [Full Text]  
  • Kamai, Y., Kakuta, M., Shibayama, T., Fukuoka, T., Kuwahara, S. (2005). Antifungal Activities of R-135853, a Sordarin Derivative, in Experimental Candidiasis in Mice. Antimicrob. Agents Chemother. 49: 52-56 [Abstract] [Full Text]  
  • Santos, C., Rodriguez-Gabriel, M. A., Remacha, M., Ballesta, J. P. G. (2004). Ribosomal P0 Protein Domain Involved in Selectivity of Antifungal Sordarin Derivatives. Antimicrob. Agents Chemother. 48: 2930-2936 [Abstract] [Full Text]  
  • Jimenez, E., Martinez, A., Aliouat, E. M., Caballero, J., Dei-Cas, E., Gargallo-Viola, D. (2002). Therapeutic Efficacies of GW471552 and GW471558, Two New Azasordarin Derivatives, against Pneumocystosis in Two Immunosuppressed-Rat Models. Antimicrob. Agents Chemother. 46: 2648-2650 [Abstract] [Full Text]  
  • Martinez, A., Ferrer, S., Santos, I., Jimenez, E., Sparrowe, J., Regadera, J., De Las Heras, F. G., Gargallo-Viola, D. (2001). Antifungal Activities of Two New Azasordarins, GW471552 and GW471558, in Experimental Models of Oral and Vulvovaginal Candidiasis in Immunosuppressed Rats. Antimicrob. Agents Chemother. 45: 3304-3309 [Abstract] [Full Text]  
  • Herreros, E., Almela, M. J., Lozano, S., Gomez De Las Heras, F., Gargallo-Viola, D. (2001). Antifungal Activities and Cytotoxicity Studies of Six New Azasordarins. Antimicrob. Agents Chemother. 45: 3132-3139 [Abstract] [Full Text]  
  • Aviles, P., Falcoz, C., Guillen, M. J., San Roman, R., Gomez De Las Heras, F., Gargallo-Viola, D. (2001). Correlation between In Vitro and In Vivo Activities of GM 237354, a New Sordarin Derivative, against Candida albicans in an In Vitro Pharmacokinetic-Pharmacodynamic Model and Influence of Protein Binding. Antimicrob. Agents Chemother. 45: 2746-2754 [Abstract] [Full Text]  
  • Aviles, P., Pateman, A., San Roman, R., Guillen, M. J., Gomez De Las Heras, F., Gargallo-Viola, D. (2001). Animal Pharmacokinetics and Interspecies Scaling of Sordarin Derivatives following Intravenous Administration. Antimicrob. Agents Chemother. 45: 2787-2792 [Abstract] [Full Text]  
  • Cuenca-Estrella, M., Mellado, E., Díaz-Guerra, T. M., Monzón, A., Rodríguez-Tudela, J. L. (2001). Azasordarins: Susceptibility of Fluconazole-Susceptible and Fluconazole-Resistant Clinical Isolates of Candida spp. to GW 471558. Antimicrob. Agents Chemother. 45: 1905-1907 [Abstract] [Full Text]  
  • Martinez, A., Regadera, J., Jimenez, E., Santos, I., Gargallo-Viola, D. (2001). Antifungal Efficacy of GM237354, a Sordarin Derivative, in Experimental Oral Candidiasis in Immunosuppressed Rats. Antimicrob. Agents Chemother. 45: 1008-1013 [Abstract] [Full Text]  
  • Shastry, M., Nielsen, J., Ku, T., Hsu, M.-J., Liberator, P., Anderson, J., Schmatz, D., Justice, M. C. (2001). Species-specific inhibition of fungal protein synthesis by sordarin: identification of a sordarin-specificity region in eukaryotic elongation factor 2. Microbiology 147: 383-390 [Abstract] [Full Text]  
  • Martinez, A., Aviles, P., Jimenez, E., Caballero, J., Gargallo-Viola, D. (2000). Activities of Sordarins in Experimental Models of Candidiasis, Aspergillosis, and Pneumocystosis. Antimicrob. Agents Chemother. 44: 3389-3394 [Abstract] [Full Text]  
  • Briones, C., Ballesta, J. P. G. (2000). Conformational changes induced in the Saccharomyces cerevisiae GTPase-associated rRNA by ribosomal stalk components and a translocation inhibitor. Nucleic Acids Res 28: 4497-4505 [Abstract] [Full Text]  
  • Aviles, P., Falcoz, C., San Roman, R., Gargallo-Viola, D. (2000). Pharmacokinetics-Pharmacodynamics of a Sordarin Derivative (GM 237354) in a Murine Model of Lethal Candidiasis. Antimicrob. Agents Chemother. 44: 2333-2340 [Abstract] [Full Text]  
  • Clemons, K. V., Stevens, D. A. (2000). Efficacies of Sordarin Derivatives GM193663, GM211676, and GM237354 in a Murine Model of Systemic Coccidioidomycosis. Antimicrob. Agents Chemother. 44: 1874-1877 [Abstract] [Full Text]  
  • Aviles, P., Aliouat, E.-M., Martinez, A., Dei-Cas, E., Herreros, E., Dujardin, L., Gargallo-Viola, D. (2000). In Vitro Pharmacodynamic Parameters of Sordarin Derivatives in Comparison with Those of Marketed Compounds against Pneumocystis carinii Isolated from Rats. Antimicrob. Agents Chemother. 44: 1284-1290 [Abstract] [Full Text]  
  • Chiou, C. C., Groll, A. H., Walsh, T. J. (2000). New Drugs and Novel Targets for Treatment of Invasive Fungal Infections in Patients with Cancer. The Oncologist 5: 120-135 [Abstract] [Full Text]  
  • Dominguez, J. M., Gomez-Lorenzo, M. G., Martin, J. J. (1999). Sordarin Inhibits Fungal Protein Synthesis by Blocking Translocation Differently to Fusidic Acid. J. Biol. Chem. 274: 22423-22427 [Abstract] [Full Text]  
  • Andriole, V. T. (1999). Current and future antifungal therapy: new targets for antifungal agents. J Antimicrob Chemother 44: 151-162 [Abstract] [Full Text]  
  • Graybill, J. R., Najvar, L., Fothergill, A., Bocanegra, R., de las Heras, F. G. (1999). Activities of Sordarins in Murine Histoplasmosis. Antimicrob. Agents Chemother. 43: 1716-1718 [Abstract] [Full Text]  
  • Justice, M. C., Ku, T., Hsu, M.-J., Carniol, K., Schmatz, D., Nielsen, J. (1999). Mutations in Ribosomal Protein L10e Confer Resistance to the Fungal-specific Eukaryotic Elongation Factor 2 Inhibitor Sordarin. J. Biol. Chem. 274: 4869-4875 [Abstract] [Full Text]  
  • Herreros, E., Martinez, C. M., Almela, M. J., Marriott, M. S., De Las Heras, F. G., Gargallo-Viola, D. (1998). Sordarins: In Vitro Activities of New Antifungal Derivatives against Pathogenic Yeasts, Pneumocystis carinii, and Filamentous Fungi. Antimicrob. Agents Chemother. 42: 2863-2869 [Abstract] [Full Text]  
  • Capa, L., Mendoza, A., Lavandera, J. L., Gómez de las Heras, F., García-Bustos, J. F. (1998). Translation Elongation Factor 2 Is Part of the Target for a New Family of Antifungals. Antimicrob. Agents Chemother. 42: 2694-2699 [Abstract] [Full Text]  
  • Domínguez, J. M., Martín, J. J. (1998). Identification of Elongation Factor 2 as the Essential Protein Targeted by Sordarins in Candida albicans. Antimicrob. Agents Chemother. 42: 2279-2283 [Abstract] [Full Text]  
  • Dominguez, J. M., Martin, J. J. (2001). Identification of a Putative Sordarin Binding Site in Candida albicans Elongation Factor 2 by Photoaffinity Labeling. J. Biol. Chem. 276: 31402-31407 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»