ABC transporters are found in all known organisms. Overexpression of ABC multidrug transporters is a major cause of clinical resistance to antibiotics, antifungal and antitumor agents. We use the yeast Pdr5 multidrug efflux pump as a model to study an important subfamily of efflux pumps found only in fungi including the highly pathogenic Candida and Cryptocoocus species. In particular we are interested in learning how these complex, polytopic proteins hydrolyze ATP in the nucleotide-binding domains and then use the resulting chemical energy to transport drugs from the transmembrane domains located a good distance away. We used a combination of suppressor genetics, site-directed mutagenesis, and biochemical assays to begin to identify a transmission signal pathway of amino acid residues and will continue that work as described in this proposal to determine whether the pathway we identify by functional studies is similar to the one proposed by purely structural studies of more conventional transporters. If this is the case, such a result would suggest that this interface is conserved among even evolutionary distant drug transporters. Such an observation might lead to the design of agents that reduce pump activity during treatment.
Broad spectrum drug resistance is a persistent problem in the treatment of infections with antibacterial and antifungal agents as well as the management of malignant tumors. The resistance is often due to genetic changes in protein detoxifying pumps known as ABC transporters which are found in all organisms. We use the yeast multidrug transporter Pdr5 to study the biochemical mechanism behind drug efflux. Pdr5 is the founding member of a subfamily of multidrug transporters that are responsible for the drug resistance of many pathogenic fungi that infect and kill immune compromised patients.
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