Submitted to: Antimicrobial Agents and Chemotherapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/21/2011
Publication Date: 2/7/2011
Citation: Xu, T., Feng, Q., Jacob, M.R., Avula, B., Mask, M.M., Baerson, S.R., Tripathi, S.K., Mohammed, R., Hamann, M.T., Khan, I.A., Walker, L.A., Clark, A.M., Agarwal, A.K. 2011. The marine sponge-derived polyketide endoperoxide plakortide F acid mediates its antifungal activity by interfering with calcium homeostasis. Antimicrobial Agents and Chemotherapy. 55(4):1611-1621. Interpretive Summary: The compound plakortide F has been isolated from marine organisms and belongs to the general class of chemicals referred to as polyketides. The compound is known to possess strong antifungal activity and therefore represents a promising natural product-based antifungal compound. Information concerning how the compound affects the function of living cells is currently lacking, and such information is critical for its possible development for commercial use. In this study, various approaches including transcriptional profiling, mutational analysis, and elemental analysis were used to gain insight into the mechanism of action of plakortide F. All of the data obtained pointed strongly to an involvement of calcium regulation as part of the mechanism through which this compound inhibits the growth of fungal cells, using the model species Saccharomyces cerevisiae as a test subject.
Technical Abstract: Plakortide F acid (PFA) is a marine-derived polyketide endoperoxide exhibiting strong inhibitory activity against several clinically important fungal pathogens. In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model organism Saccharomyces cerevisiae, to investigate the mechanism of action of this compound. PFA elicited a transcriptome response highly suggestive of a Ca2+ imbalance, affecting a large number of genes known to be responsive to altered cellular calcium levels. Furthermore, several lines of evidence were obtained which supported a role for Ca2+: (i) Ca2+ transporter mutants were hypersensitive to PFA, (ii) loss or inhibition of calcineurin function enhanced PFA activity, and (iii) PFA treatment increased intracellular calcium levels. Collectively, our results indicate that PFA mediates its antifungal activity by perturbing Ca2+ homeostasis, thus representing a potentially novel mechanism distinct from that of currently used antifungal agents.