The resistant Z bailii sub-population

The resistant Z. bailii sub-population Bortezomib clinical trial cultured in 6 mM sorbic acid showed a considerably reduced uptake of 14C-acetic acid, the plateau level of uptake being ~ 4-fold lower than in the bulk Z. bailii population. These data confirm that the resistant sub-population of Z. bailii took up a lower dose of weak-acid, thus potentially accounting for the high level of resistance. Uptake, and cytoplasmic accumulation, of weak acids in yeast is primarily controlled by the differential between the media pH and intracellular pH. Since the media pH was constant at pH 4.0 in

all experiments, it is probable that the lower uptake of acetic acid in the resistant sub-population (Fig. 5) was due to a consistently lower intracellular pH in sub-populations grown in any weak acid. Intracellular

pH in cells within the Z. bailii population was therefore determined by flow cytometry on CFDASE-treated cells, stained in the growth media to avoid anomalies caused by cell washing. Results confirmed that the mean intracellular pH of bulk populations of exponentially-growing Z. bailii and S. cerevisiae were similar ( Fig. 6). In contrast, the mean intracellular pH values of the resistant sub-populations of Z. bailii were consistently lower by 0.4–0.8 pH units, Paclitaxel cost depending on the weak acid (sorbic acid p = 0.00271; benzoic acid p = 0.00436; acetic acid p = 0.00857). These data on the lower internal pH of sub-populations grown in weak acid are consistent with the observed Astemizole reduction in weak-acid uptake ( Fig. 5) and are discussed below. The data presented in this paper confirm the high resistance of all 38 tested strains of Z. bailii to weak-acid preservatives. Further tests showed that a representative strain of Z. bailii was resistant to a wide variety of lipophilic and hydrophilic weak acids. On average ~ 3-fold more weak-acid was required to inhibit growth of Z bailii than S. cerevisiae. No enhanced resistance was found to alcohols, aldehydes or esters. Previous reports of Z. bailii resistance to alkanols ( Fujita et al., 2008, Goswell, 1986 and Thomas

and Davenport, 1985) remain valid, but comparable resistance is also found in S. cerevisiae and therefore those data do not address the issue of relative resistance between Z. bailii and other yeasts. Resistance in Z. bailii was shown to a wide variety of weak acids. Degradation of acids is unlikely to be a significant factor in resistance, due to the diversity of acid structures (including adamantane carboxylic acid), the lack of growth rate restoration in sub-populations, cross-resistance between dissimilar acids, and earlier studies showing that acid metabolism was insufficient to determine resistance ( Warth, 1977). In Z. bailii, extreme weak-acid resistance was most probably due to the presence of low numbers of resistant cells in the Z. bailii bulk populations.

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