Pleiotropic drug resistance (PDR) plasma membrane transporters mediate xenobiotic efflux from the cells and thereby help pathogenic microorganisms to withstand antimicrobial therapies. Given that xenobiotic efflux is an energy-consuming process, cells with upregulated PDR can be sensitive to perturbations in cellular energetics. Protonophores dissipate proton gradient across the cellular membranes and thus increase ATP spendings to their maintenance. We hypothesised that chronic exposure of yeast cells to the protonophores can favour the selection of cells with inactive PDR. To test this, we measured growth rates of the wild type Saccharomyces cerevisiae and PDR-deficient Δpdr1Δpdr3 strains in the presence of protonophores carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), pentachlorophenol (PCP) and niclosamide (NCA). Although the protonophore-induced respiration rates of these two strains were similar, the PDR-deficient strain outperformed the control one in the growth rate on non-fermentable carbon source supplemented with low concentrations of FCCP. Thus, active PDR can be deleterious under conditions of partially uncoupled oxidative-phosphorylation. Furthermore, our results suggest that tested anionic protonophores are poor substrates of PDR-transporters. At the same time, protonophores imparted azole tolerance to yeasts, pointing that they are potent PDR inducers. Interestingly, protonophore PCP led to a persistent increase in the levels of a major ABC-transporter Pdr5p, while azole clotrimazole induced only a temporary increase. Together, our data provides an insight into the effects of the protonophores in the eukaryotes at the cellular level and support the idea that cells with activated PDR can be selected out upon conditions of energy limitations.

多效药物耐药性（PDR）质膜转运蛋白介导细胞异种外排，从而帮助病原微生物经受抗菌治疗。鉴于异种外排是一个耗能的过程，PDR上调的细胞可能对细胞能量学中的扰动敏感。质子载体消散了跨细胞膜的质子梯度，因此增加了其维护所需的ATP支出。我们假设酵母细胞长期暴露于质子载体可以促进具有非活性PDR的细胞的选择。为了测试这一点，我们测量了野生型酿酒酵母和缺乏PDR的Δpdr1Δpdr3的增长率在质子体羰基氰化物-对-三氟甲氧基苯基hydr（FCCP），五氯苯酚（PCP）和烟酰胺（NCA）的存在下分离菌株。尽管这两个菌株的质子体诱导呼吸速率相似，但在补充了低浓度FCCP的不可发酵碳源的生长速率上，PDR缺陷型菌株的表现优于对照菌株。因此，活性PDR在部分未偶联的氧化磷酸化的条件下可能是有害的。此外，我们的结果表明，测试的阴离子质子载体是PDR转运蛋白的较差底物。同时，质子载体赋予酵母对唑的耐受性，指出它们是有效的PDR诱导剂。有趣的是，质子载体PCP导致主要ABC转运蛋白Pdr5p的水平持续增加，吡咯克霉唑只是暂时性的增加。在一起，我们的数据提供了真核生物中质子载体在细胞水平上的作用的见解，并支持了可以在能量限制条件下选择具有激活PDR的细胞的想法。