Cross‐species discovery of syncretic drug combinations that potentiate the antifungal fluconazole

Molecular Systems Biology

Michaela Spitzer²  Emma Griffiths¹  Kim M Blakely¹  Jan Wildenhain²  Linda Ejim¹  Laura Rossi¹  Gianfranco De Pascale¹  Jasna Curak¹  Eric Brown¹  Mike Tyers² 

[1] Michael G. DeGroote Institute for Infectious Disease Research and the Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada;Wellcome Trust Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, UK

关键词: antifungal;    combination;    pathogen;    resistance;    synergism;   

DOI  :  10.1038/msb.2011.31

来源: Wiley

【 摘 要 】

Resistance to widely used fungistatic drugs, particularly to the ergosterol biosynthesis inhibitor fluconazole, threatens millions of immunocompromised patients susceptible to invasive fungal infections. The dense network structure of synthetic lethal genetic interactions in yeast suggests that combinatorial network inhibition may afford increased drug efficacy and specificity. We carried out systematic screens with a bioactive library enriched for off-patent drugs to identify compounds that potentiate fluconazole action in pathogenic Candida and Cryptococcus strains and the model yeast Saccharomyces. Many compounds exhibited species- or genus-specific synergism, and often improved fluconazole from fungistatic to fungicidal activity. Mode of action studies rev

【 授权许可】

CC BY-NC-SA   
Copyright © 2011 EMBO and Macmillan Publishers Limited

Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.