Yeast models to study sulfadrug resistance in pathogens.
Ian Macreadie (1), Peter Iliades (1), Steven Meshnick (2)
(1) Health Sciences and Nutrition, CSIRO, 343 Royal Parade, Parkville, Vi, 3052, Australia; (2) Department of Microbiology, University of North Carolina, Chapel Hill, NC, USA
Sulfadrugs, the first chemically-synthesised antibiotics, have saved millions of lives over the past seven decades. Their effectiveness, however, is declining due to the emergence of drug resistance. Studies of sulfadrug resistance in the major pathogens, Pneumocystis and Plasmodium are impossible or difficult so our work has focused on development of yeast models to address the action of sulfa drugs, the mechanisms of drug resistance and to develop new strategies for treatment. The sulfadrugs mimic p -aminobenzoate which condenses with dihydropteridine pyrophosphate to make dihydropteroate. In yeast dihydropteroate synthase (DHPS) is encode by FOL1, a gene that encodes two upstream enzymes, dihydroneopterin aldolase and hydroxymethyldihydropterin pyrophosphate kinase. The enzyme, dihydrofolate synthase adds glutamate to dihydropteroate and is encoded by FOL3. Yeast fol1 and fol3 deletion mutants show that each enzyme involved in folate synthesis is essential. The mutants serve as tools for studying the action of sulfadrugs. In addition reverse engineering of DHPS mutations associated with sulfadrug resistance and gene expression analyses have enabled processes in the development of resistance to be modelled.