BALZI E; Interscience Conference on Antimicrobial Agents and Chemotherapy.

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 1999 Sep 26-29; 39: 747 (abstract no. 473).

Catholic Univ. of Louvain, Louvain-la-Neuve, Belgium.

Multidrug resistance to fungicides is of rising concern, particularly in infected immunocompromised patients. The model yeast Saccharomyces cerevisiae, as well as the most common pathogenic fungus Candida albicans, have developed a multitude of permeases (belonging to the Major Facilitators Superfamily) and pumps (belonging to the ATP-Binding-Cassette Superfamily) for the efflux of multiple drugs. In addition, the yeast S. cerevisiae has revealed a complex network of pleiotropic drug resistance genes (PDR) controlled by the transcription regulators Pdr1p and Pdr3p. Using genetic and bioinformatics tools in combination with genomic microarray analysis, we have systematically identified the multiple transcriptional targets of these two major regulators of multidrug resistance. These new targets comprise ATP-dependent and proton-motive force dependent permeases as well as genes more generally involved in lipid metabolism and stress defence. This indicates a major, and partly overlapping, role for Pdr1p and Pdr3p in the defence of yeast against cytotoxic stress, expressed via the control of diversified, yet coherent, determinants of multidrug transport across cell membranes. We have generated strains simultaneously deleted of up to 8 ABC drug-pumps, 5 MFS-drug-permeases and 2 PDR regulator genes in different combinations. We have screened 350 toxic compounds and found that the three major ABC drug-pumps PDR5, SNQ2 and YOR1 mediate resistance to most of them, including new classes of clinically- and agriculturally-relevant antifungals, antibiotics, herbicides and other compounds. Extremely promiscuous and overlapping, yet distinct, profiles of drug-specificity were found for these three major yeast drug-transporters. The implications of these findings for the development of new fungicides is discussed. Prasad, R., De Wergifosse, P. Goffeau, A. and Balzi, E. (1994) Molecular cloning and characterization of a novel gene of Candida albicans, CDR1, conferring multiple drug resistance to drugs and antifungals. Current Genet. 27, 320-329. DeRisi, J., van den Hazel, B., Jonniaux, J.L., Do Valle Matta, M.A., Marc, P., Balzi, E., Brown, P., Jacq, C. and Goffeau, A. Genome microarray analysis of transcriptional activation of multidrug resistance in yeast. Submitted. Goffeau, A., Park, J., Paulsen, I.T, Jonniaux, J.L., Dihn, T., Mordant, P. and Saier, M.H. (1997) Mutidrug-resistant transport proteins in yeast: complete inventoy and phylogenetic characterization of yeast open reading frames within the major facilitator superfamily. Yeast 13, 43-54. Decottignies, A. and Goffeau, A. (1998) Complete inventory of the yeast ABC proteins. Nature Genet.15, 137-145. Kolaczkowski, M., Kolaczkowska, A., Luczynski, J., Witek, S. and Goffeau, A. (1998) In vivo characterization of the drug resistance profiles of the major ABC transporters and other components of the yeast pleiotropic drug resistance network. Microbial Drug Resistance 4, 143-158.

Publication Types:

• Meeting Abstracts

Keywords:

• ATP-Binding Cassette Transporters
• Antifungal Agents
• Candida albicans
• Carrier Proteins
• Cloning, Molecular
• Drug Resistance, Microbial
• Drug Resistance, Multiple
• Fungal Proteins
• Humans
• Membrane Transport Proteins
• Open Reading Frames
• Saccharomyces cerevisiae
• Transcription, Genetic
• genetics

Other ID:

• GWAIDS0008493

UI: 102245990

From Meeting Abstracts