This study investigated the roles of two multidrug resistance transporters, Pdr18 and Tpo1, in conferring resistance to the fungicide mancozeb in the yeast Saccharomyces cerevisiae. Both PDR18 and TPO1 genes were found to be up-regulated when yeast cells were exposed to mancozeb, and deletion of either gene decreased resistance. Exposure to mancozeb increased plasma membrane permeability and decreased potential to a greater degree in Δpdr18 cells. Pdr18 deletion also lowered ERG24 transcription related to ergosterol biosynthesis under mancozeb stress.

1. Abstract
The role of multidrug resistance (MDR) transporters of the Major Facilitator Superfamily (MFS)
and of the ATP binding cassette (ABC) superfamily in cell defense against chemical stress may
be indirect due to their physiological roles, inducing an altered intracellular accumulation of toxic
compouns.
In the present study, the yeast Saccharomyces cerevisiae was used as an experimental model
system to elucidate the role of the plasma membrane MDR transporters, the ABC Pdr18, and
the MFS Tpo1, as determinants of resistance to the agricultural fungicide mancozeb.
Both PDR18 and TPO1 were found to be up-regulated and confirmed to confer resistance in
yeast cells exposed to mancozeb. The up-regulation of TPO1 transcription under mancozeb
stress was found to be dependent of Yap1, the major regulator of oxidative stress resistance in
yeast.
Pdr18 was previously proposed to mediate ergosterol incorporation in the yeast plasma
membrane and Tpo1 was proposed to be involved in polyamine homeostasis, physiological
roles that influence plasma membrane properties. Under mancozeb imposed stress, yeast cells
exhibited an increased plasma membrane permeability and a decreased plasma membrane
potential. These effects were shown to be highly intensified in the ∆pdr18 background. The
deletion of PDR18 was found to have an effect in the ergosterol biosynthetic pathway, leading
to lower levels of ERG24 transcription in cells exposed to mancozeb. ERG9 transcription was
found to be up-regulated in the ∆tpo1 cells, however, in response to mancozeb no significant
differences were found.
Key words: Saccharomyces cerevisiae; multidrug resistance (MDR); resistance to mancozeb;
plasma membrane transporters; ATP-binding cassette (ABC) superfamily; Major Facilitator
Superfamily (MFS); Pdr18; Tpo1