Extracellular pH Dictates the Antifungal Activity for a Unique Class of Glucan Synthase Inhibitors

l. A. Harrigan, j. M. Bauer, m. Zhong, z. Jia, J. W. Wilks

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Background: We noted pH-dependent activities for a novel class of small molecular weight glucan synthase (GS) inhibitors exemplified by N-{2-[(1S)-6-bromo-3,4-dihydro-1H-isochromen-1-yl]ethyl}-1-(4-bromophenyl)-N-methyl-4-piperidinamine. We sought to define the antifungal activities of these GS inhibitors over a range of H+ concentrations. Methods: Candida albicans, Candida krusei, Saccharomyces cerevisiae or Aspergillus fumigatus cultures were initiated in media buffered to differ at increments of 0.5 pH units over a pH range from 3-9. Fungal growth was assessed by optical density measurements after 24 hours of incubation. Results: C. albicans grew robustly over the entire pH range, although C. krusei growth was reduced 40% at alkaline pH values. S. cerevisiae grew well at all H+ concentrations except when pH was ≷8.5. A. fumigatus grew best in the pH range from 4-7 and less well at the acidic and basic extremes. Depending upon the pH of the medium, GS inhibitors either had no effect on fungal growth or completely inhibited proliferation. Complete growth inhibition was seen at pH values from 6-7 for S. cerevisiae and A. fumigatus, while complete inhibition of C. albicans and C. krusei growth occurred at a more alkaline pH (7.5-8.5). The pKa values determined for several GS inhibitors were similar with a pKa ~2.5 for the N-atom in the piperidine moiety and pKa~9.0 for the tertiary amine linking the isochroman moiety with the piperidine. The tertiary amine will be totally ionized at pH values 8804;6, likely rendering the GS inhibitors poorly adherent to the amphiphilic cell surface and membrane impermeant. Differences in antifungal activity between compounds at a given pH could be explained by differences in hydrophobicity. Small activity differences between species imply a biological contribution to the antifungal action of the GS inhibitors, but its basis remains undefined. Conclusion: Antifungal activity for this class of GS inhibitors is largely determined by the ionization status of the tertiary amine.

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    • ICAAC 42nd