Multidrug resistance in fungi.

One of the major advances serving to define the beginning of the era of modern medicine was the development of penicillin in the early 1940s as the first widely used antibiotic effective against microorganisms (reviewed in reference 111). In what has become an all-too-common trend, antibiotic-resistant isolates emerged soon after the large-scale use of penicillin to treat bacterial infections (7). This cycle has been repeated many times over the years as new antibiotics are generated (reviewed in reference 66). This has led to obvious concern about the continuing efficacy of antibiotics to control infectious disease (1). Resistance to antibiotics in pathogenic fungi is a problem of special importance in the control of infections caused by these organisms. The same extraordinary conservation of the basic eukaryotic cellular biology exhibited by fungal and animal cells that has allowed these smaller eukaryotes to serve as outstanding model organism limits the range of fungus-specific antibiotics that have been described. In addition, mutant fungi are readily isolated, both in the laboratory and in the clinic, that demonstrate resistance to a wide range of antibiotics beyond that initially used for treatment. This broad-spectrum drug tolerance is referred to as multidrug resistance and occurs in organisms ranging from bacteria to humans (67). The limited number of antifungal drugs makes this phenotype an acute problem in the chemotherapeutic eradication of fungal infections. Much of our understanding of multidrug resistance in fungi comes from studies in the generally nonpathogenic yeast Saccharomyces cerevisiae, in which the multidrug-resistant phenotype is referred to as pleiotropic drug resistance or Pdr (see reference 5 for a historical review). Genes influencing this phenotype are typically designated PDR loci. With the development of powerful new genetic and molecular biological techniques, workers have provided important new insights into the physiology of multidrug resistance from experiments performed directly in pathogenic organisms. This review focuses on providing an introduction to the various pathways influencing multidrug resistance in S. cerevisiae and compares these pathways to similar ones from pathogenic fungi such as Candida albicans, Candida glabrata, and Aspergillus fumigatus. PLEIOTROPIC DRUG RESISTANCE IN SACCHAROMYCES CEREVISIAE