Saccharomyces cerevisiae: Population Divergence and Resistance to Oxidative Stress in Clinical, Domesticated and Wild Isolates

BACKGROUND: Saccharomyces cerevisiae has been associated with human life for millennia in the brewery and bakery. Recently it has been recognized as an emerging opportunistic pathogen. To study the evolutionary history of S. cerevisiae, the origin of clinical isolates and the importance of a virulence-associated trait, population genetics and phenotypic assays have been applied to an ecologically diverse set of 103 strains isolated from clinics, breweries, vineyards, fruits, soil, commercial supplements and insect guts. METHODOLOGY/PRINCIPAL FINDINGS: DNA sequence data from five nuclear DNA loci were analyzed for population structure and haplotype distribution. Additionally, all strains were tested for survival of oxidative stress, a trait associated with microbial pathogenicity. DNA sequence analyses identified three genetic subgroups within the recombining S. cerevisiae strains that are associated with ecology, geography and virulence. Shared alleles suggest that the clinical isolates contain genetic contribution from the fruit isolates. Clinical and fruit isolates exhibit high levels of recombination, unlike the genetically homogenous soil isolates in which no recombination was detected. However, clinical and soil isolates were more resistant to oxidative stress than any other population, suggesting a correlation between survival in oxidative stress and yeast pathogenicity. CONCLUSIONS/SIGNIFICANCE: Population genetic analyses of S. cerevisiae delineated three distinct groups, comprising primarily the (i) human-associated brewery and vineyard strains, (ii) clinical and fruit isolates (iii) and wild soil isolates from eastern U.S. The interactions between S. cerevisiae and humans potentiate yeast evolution and the development of genetically, ecologically and geographically divergent groups

Investigating the influence of relevant pharmacogenetic variants on the pharmacokinetics and pharmacodynamics of orally administered docetaxel combined with ritonavir

The anticancer drug docetaxel exhibits large interpatient pharmacokinetic and pharmacodynamic variability. In this study, we aimed to assess the functional significance of 14 polymorphisms in the CYP3A, CYP1B1, ABCB1, ABCC2, and SLCO1B3 genes for the pharmacokinetics and pharmacodynamics of oral docetaxel, co-administered with ritonavir. None of the tested CYP3A, ABCB1, ABCC2, and SLCO1B3 genotypes and diplotypes showed a significant relation with an altered bioavailability or clearance of either docetaxel or ritonavir. Similarly, no clear effect of CYP1B1 genotype on clinical outcomes was observed in a subgroup of non-small cell lung cancer (NSCLC) patients. Our post hoc power analysis indicated that our pharmacogenetic–pharmacokinetic analysis was only powered for relatively high effect sizes, which were to be expected given the high interpatient variability. This makes it unlikely that future studies will explain the high observed interpatient variability in oral docetaxel pharmacokinetics as a result of any of these separate polymorphisms and diplotypes